Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:7][CH2:8][Cl:9])[CH2:5][CH3:6])[CH3:3].[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1.[OH-].[Na+]>O.C(O)C>[ClH:9].[CH2:5]([N:4]([CH2:7][CH2:8][O:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]2[CH:23]=[CH:24][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:21][CH:20]=1)[CH2:2][CH3:3])[CH3:6]
Reactant: CCN(CC)CCCl
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCN(CC)CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 82.6 %

Procedure:
A solution of 13.2 g (0.075 mol) of 2-(N,N-diethylamino)-1-chloroethane hydrochloride in 30 ml of water is run over the course of 30 minutes into a solution, kept at about 60° C., of 15 g (0.068 mol) of p-(p-chlorophenoxy)-phenol and 6.3 g (0.157 mol) of sodium hydroxide pellets in 20 ml of water and 20 ml of ethanol. The mixture is heated to the reflux temperature for 1 hour and the ethanol is evaporated under reduced pressure. The aqueous phase is extracted with diethyl ether and the organic phase obtained is washed with water until neutral, dried over dry sodium sulphate and evaporated to dryness under reduced pressure. The oily residue is treated in a solution of hydrogen chloride in diethyl ether, to give 20 g of a white powder. Recrystallisation from ethyl acetate gives 18 g of CRL 40 330
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][O:11][CH3:12])[C:4]=1[CH:13]([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15].C([Li])CCC.CCCCCC.CC1C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1>[C:14]([CH:13]1[C:4]2[C:3](=[CH:8][CH:7]=[CH:6][C:5]=2[O:9][CH2:10][O:11][CH3:12])[CH2:2][O:18]1)([CH3:15])([CH3:16])[CH3:17]
Reactant: COCOc1cccc(CO)c1C(O)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1cccc2c1C(C(C)(C)C)OC2
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
To a solution of 1-[2-(hydroxymethyl)-6-(methoxymethoxy)phenyl]-2,2-dimethyl-propan-1-ol (Intermediate 3, 300 mg, 1.18 mmol) in dry THF (5 mL) at OC butyllithium 1.6M solution in hexane (0.74 ml, 1.18 mmol) was slowly added and the reaction mixture was stirred for 5 minutes at the same temperature. 4-methylbenzenesulfonyl chloride (224.89 mg, 1.18 mmol) dissolved in THF (1 ml) was slowly added and the reaction mixture was stirred for 5 minutes at the same temperature. Butyllithium 1.6M solution in hexane (0.74 ml, 1.18 mmol) was slowly added and the reaction mixture was stirred for 30 minutes at at 0° C. The reaction was quenched with water (1 ml), diluted with brine (10 ml) and extracted with ethyl acetate (2×15 ml). The organic layer was dried (Na2SO4), filtered and evaporated and The residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 25 g as column and cyclohexane/ethyl acetate from 100:0 to 70:30 as eluent affording the title compound (260 mg) as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:12][C@@H:11]2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[N:5]=[C:4]([CH3:20])[N:3]=1.[CH3:21][C:22]1[S:26][C:25]([CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:24][N:23]=1.CC(C)([O-])C.[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.N#N>CC(O)(CC)C.C(OCC)(=O)C.C([O-])(O)=O.[Na+].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]>[CH3:21][C:22]1[S:26][C:25]([CH2:27][N:28]([C:2]2[CH:7]=[C:6]([O:8][CH2:9][C@H:10]3[CH2:12][C@@H:11]3[C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=3)[N:5]=[C:4]([CH3:20])[N:3]=2)[C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[N:24][N:23]=1
Reactant: Cc1ccc([C@H]2C[C@@H]2COc2cc(Cl)nc(C)n2)nc1
Reactant: Cc1nnc(CNC(=O)OC(C)(C)C)s1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: CCC(C)(C)O
Product: Cc1ccc([C@H]2C[C@@H]2COc2cc(N(Cc3nnc(C)s3)C(=O)OC(C)(C)C)nc(C)n2)nc1
Temperature: 60 °C
Yield: 69.3 %

Procedure:
A solution of 2-1 (100 mg, 0.35 mmol), tert-butyl ((5-methyl-1,3,4-thiadiazol-2-yl)methyl)carbamate (119 mg, 0.52 mmol; for preparation, see D. C. Pryde et al. J. Med. Chem. 2006, 49, 4409-4424), 1 M potassium tert-butoxide (1.03 mL in THF) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (14.6 mg, 0.035 mmol) in 2-Methyl-2-butanol (1.7 ml) was purged with N2 for 5 min. Tris(dibenzylideneacetone)-dipalladium(0) (31.6 mg, 0.035 mmol) was added and the mixture was heated at 60° C. for 1 hour. The reaction was cooled to room temperature and diluted with ethyl acetate and sat. NaHCO3. The organic phase was washed with water, brine and concentrated. The residue was purified by flash column chromatography using a 20-60% ethyl acetate/hexane gradient gave 2-2 as a colorless oil (117 mg, 70%). MS (M+H)+: observed=483.10, calculated=483.21.
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:25])([CH3:24])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][N:16]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[N:17]2)[N:14]=1)([CH3:6])([CH3:5])[CH3:4].[NH4+].[Cl-]>CCO.O.[Fe]>[C:3]([SiH2:7][O:8][C:9]([CH3:25])([CH3:24])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][N:16]2[CH:20]=[C:19]([NH2:21])[CH:18]=[N:17]2)[N:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(Cn2cc([N+](=O)[O-])cn2)co1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[SiH2]OC(C)(C)c1nc(Cn2cc(N)cn2)co1
Temperature: 75 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-4-(4-nitro-pyrazol-1-ylmethyl)-oxazole (408 mg, 1.20 mmol), iron powder (204 mg, 3.62 mmol) and NH4Cl (326 mg, 6.03 mmol) in a mixture of EtOH (6.0 mL) and water (3.0 mL) was stirred at 75° C. for 45 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. The residue was redissolved in CH2Cl2 (20 mL), dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as an orange oil. TLC: rf (EA)=0.20. LC-MS-conditions 02: tR=0.81 min; [M+H]+=309.07.
Reaction SMILES: CN(C)C1C=CC=CC=1.NC(C(O)=O)CCCC([NH:17][CH:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([O-:37])=[O:36])=[C:22]([CH2:25][S:26][C:27]3[N:31]([CH2:32][CH:33]=[CH2:34])[N:30]=[N:29][N:28]=3)[CH2:23][S:24][C@H:19]12)=O.[NH4+].C[Si](Cl)(C)C.P(Cl)(Cl)(Cl)(Cl)Cl.C(OCCO)C>O.C(Cl)Cl>[NH2:17][CH:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([OH:37])=[O:36])=[C:22]([CH2:25][S:26][C:27]3[N:31]([CH2:32][CH:33]=[CH2:34])[N:30]=[N:29][N:28]=3)[CH2:23][S:24][C@H:19]12
Reactant: C=CCn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)CCCC(N)C(=O)O)[C@H]2SC1
Agent: C[Si](C)(C)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOCCO
Solvent: CN(C)c1ccccc1
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
N,N-Dimethylaniline (18.2 ml) was added to a mixture of ammonium 7-(5-amino-5-carboxyvaleramido)-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (10.0 g), trimethylsilyl chloride (20.9 ml) and methylene chloride (75 ml), and the mixture was stirred under reflux for 2.5 hours. Phosphorus pentachloride (5.83 g) was added thereto at -30° to -35° C. and the mixture was stirred for 2 hours at the same temperature. 2-Ethoxyethanol (38 ml) was added dropwise thereto at the same temperature and the mixture was stirred for 1 hour at the same temperature. Water (80 ml) was added thereto at -5° to -10° C. over 10 minutes and the resulting mixture was stirred for 5 minutes at the same temperature. The aqueous layer was separated and adjusted to pH 4.2 with 28% aqueous solution of ammonia. Precipitates were collected by filtration, washed with 70% aqueous acetone (40 ml) and methanol (40 ml), and dried to give 7-amino-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (4.1 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:17]([O:19]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:18]>O1CCOCC1>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([C:17](=[O:19])[CH3:18])=[N:3][CH:4]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CSc1ccc(Br)nc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CSc1ccc(C(C)=O)nc1

Procedure:
To a stirring solution of 2-bromo 5-methylsulfanyl pyridine (3.05 g 14.9 mmol), triethylamine (2.10 mL, 14.9 mmol) and (1-ethoxyvinyl)tributyl tin (10.1 mL, 29.8 mmol) in anhydrous 1,4-dioxane (100 mL), was added dichlorobis(triphenylphosphine) palladium (II) (5 mol %, 0.524 g) and the reaction heated to reflux under nitrogen for 18 hours. After cooling, dichlorobis(triphenylphosphine) palladium (II) was added and the reaction heated under nitrogen for a further 18 hours. The reaction was allowed to cool and-the reaction mixture partitioned between saturated aqueous potassium fluoride solution (250 mL) and diethyl ether (250 mL). The ether layer was separated and 2N hydrochloric acid (250 mL) added. The acid layer was separated and sodium carbonate added portionwise until the solution reached pH 8. The solution was extracted with dichloromethane (3×200 mL). The organic extracts were combined and the solvent removed. The residue was partitioned between cyclohexane (60 ml) and acetonitrile (60 mL). The acetonitrile layer was separated and the solvent removed to yield a brown solid. The crude product was purified by flash column chromatography (cyclohexane:ethyl acetate, 95:5) to afford the title compound as a white solid:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[C:10](OCC)(=[O:15])[CH2:11][C:12]([CH3:14])=O>>[OH:15][C:10]1[C:5]2[C:3](=[C:2]([F:1])[CH:8]=[CH:7][C:6]=2[F:9])[N:4]=[C:12]([CH3:14])[CH:11]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1cc(F)ccc1F
Product: Cc1cc(O)c2c(F)ccc(F)c2n1
Temperature: 180 °C
Reaction time: 5 h

Procedure:
A mixture of 2,5-difluoroaniline (10.0 g), ethyl acetoaceate (9.85 ml) and polyphosphoric acid (62 ml) were heated with stirring at 180° C. for 5 h. The mixture was cooled to room temperature and neutralised with dilute NH4OH/ice. The title compound precipitated and was separated by filtration to give compound identical spectroscopically with a sample prepared by the two stage process described above.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:18][NH:19][O:20][CH3:21].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH3:18][N:19]([O:20][CH3:21])[C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 22 h
Yield: 87.7 %

Procedure:
A mixture of N-Boc-L-leucine (2.47 g), N,O-dimethylhydroxylamine hydrochloride (1.09 g), 1-hydroxybenzotriazole monohydrate (1.51 g), and N-methylmorpholine (1.21 mL) was dissolved in DMF (40 mL), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.14 g) was added at 0° C. and the mixture was stirred at 0° C. for 2h, then at room temperature for 22 h. The reaction was quenched with water (100 mL) and the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with aqueous 10% HCl, saturated NaHCO3, and brine, then dried over anhydrous MgSO4, filtered, and evaporated to afford the product (2.57 g) as an oil.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:14]([O:15][CH3:16])[C@H:13]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:12][C@@H:11]1/[CH:35]=[CH:36]/[P:37]([O:43]C(C)C)([O:39]C(C)C)=[O:38])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC1NC(=O)C2N=CN(C3OC(C=CP(O)(O)=O)C(OC(=O)C4C=CC=CC=4)C3OC)C=2N=1)(=O)C(C)C>>[C:27]([NH:26][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[C:23]=1[N:24]=[CH:25][N:17]2[C@@H:13]1[O:12][C@H:11](/[CH:35]=[CH:36]/[P:37](=[O:38])([OH:39])[OH:43])[C@@H:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:14]1[O:15][CH3:16])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](/C=C/P(=O)(OC(C)C)OC(C)C)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Agent: COC1C(OC(=O)c2ccccc2)C(C=CP(=O)(O)O)OC1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Product: CO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](/C=C/P(=O)(O)O)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Yield: 47.5 %

Procedure:
Compound 21.3 (124 mg, 47.5% yield) was synthesized from compound 21.2 (300 mg, 0.462 mmol) using the procedure described for the synthesis of compound 16.8.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH2:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:23][N:22]([CH3:21])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.2 g, 0.72 mmol) in dry DCM (10 mL) were added tert-butyl 1-methylhydrazinecarboxylate 176 (0.16 g, 1.08 mmol), 1-hydroxybenzotriazole (0.15 g, 1.08 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g, 1.08 mmol) and 4-dimethylaminopyridine (0.13 g, 1.08 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl 2-{[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylate 177 (0.25 g, 86%) as a clear thick oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][N:8]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:7]1=[O:30].O>CN(C)C=O>[C:16]([O:15][C:13]([N:11]1[CH2:12][C@@H:6]([N:1]=[N+:2]=[N-:3])[C:7](=[O:30])[N:8]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH2:9][C@@H:10]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC(Br)C(=O)N(CC2CC2)CC1c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C(=O)N(CC2CC2)C[C@@H]1c1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sodium azide (0.841 g, 12.9 mmol) was added to a solution of tert-butyl 6-bromo-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-diazepane-1-carboxylate (0.609 g, 1.43 mmol) in N,N-dimethylforamide (10 mL) and heated to 70° C. After 1 h, the mixture was allowed to cool to ambient temperature and water was added. The mixture was extracted with ethyl acetate, washed with water (3×), saturated brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (20% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gave 170 mg of the trans isomer and 30 mg of the cis isomer. MS 386 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]([C:11](=O)[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(O)(=O)C.C(N)=[NH:19].CC[O-].[Na+]>CCO>[CH3:12][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:2]=[CH:1][N:19]=1
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: N=CN
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cncnc1C
Yield: 31 %

Procedure:
Intermediate 51 (9.7 g, 52.4 mmol) and Formamidine acetate (5.4 g, 52.4 mmol), were dissolved in EtOH and added NaOEt (3.6 g, 52.4 mmol). This mixture was refluxed for 6 h. After that, ethanol removed on rotavapour followed by work-up (AcOEt/H2O) to obtain the crude. Crude was purified by column chromatography using 60-120 mesh silicagel and AcOEt and Petether (25:75) as eluent to obtain the title compound (2.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[CH3:24][N:25]1[C:29]([Sn](CCCC)(CCCC)CCCC)=[CH:28][N:27]=[C:26]1[CH:43]=[O:44].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCOCC1.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>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:29]3[N:25]([CH3:24])[C:26]([CH:43]=[O:44])=[N:27][CH:28]=3)[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C=O)n1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4cnc(C=O)n4C)sc23)c(Cl)cc1Cl
Temperature: 110 °C
Yield: 52.2 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (443.2 mg, 0.93 mmol), 1-methyl-5-(tributylstannyl)-1H-imidazole-2-carbaldehyde (743.1 mg, 1.86 mmol), dichlorobis(triphenylphosphine)palladium(II) (33.0 mg, 0.047 mmol) and triethylamine (103.2 mg, 1.02 mmol) in 8.0 mL of 1,4-dioxane is heated at 110° C. for 3 hours. After cooling, the mixture is treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in dichloromethane to 50% ethyl acetate in dichloromethane to provide 222.7 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(2-formyl-1-methyl-1H-imidazol-5-yl)thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp 225-227° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 4.08 (d, 3H), 7.41 (s, 1H), 7.63 (s, 1H), 7.77 (s, 1H), 7.90 (s, 1H), 8.67 (s, 1H), 9.77 (s, 1H), 9.87 (s, 1H); MS 458.1, 460.1 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH:5]([OH:7])[CH3:6].N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd].C1C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])/[CH:3]=[CH:4]\[CH:5]([OH:7])[CH3:6]
Reactant: [H][H]
Reactant: CC(O)C#C[Si](C)(C)C
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: c1ccccc1
Product: CC(O)/C=C\[Si](C)(C)C

Procedure:
A solution of 94.15 parts by weight of 4-(trimethylsilyl)-3-butyn-2-ol (II) in 940 parts by volume of benzene and 4.7 parts by volume of quinoline is hydrogenated at a constant pressure of 2 p.s.i. in the presence of 9.4 parts by weight of 5% palladium on barium sulfate until one equivalent of hydrogen is consumed. The catalyst is removed and the solution is washed twice with 100 parts per volume of 5% aqueous hydrochloric acid and then with water. After drying over sodium sulfate, the solvent is removed and the residue is distilled at 33°-39° C./0.3 mm to give cis-4-(trimethylsilyl)-3-buten-2-ol (III) which has the following structural formula: ##STR9##
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:14][CH3:15].N1C=CC=CC=1.[C:22](Cl)([Cl:24])=[O:23]>O1CCCC1.C1C=CC=CC=1>[Cl:24][C:22]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:14][CH3:15])=[O:23]
Reactant: COc1cc(OC)c2ccccc2c1O
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1cc(OC)c2ccccc2c1OC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.27 g of 1-hydroxy-2,4-dimethoxynaphthalene, prepared as shown in Preparations 7 and 8, in 50 ml of tetrahydrofuran and 1 ml of pyridine is added 10 ml of a solution of 12.5% phosgene in benzene. The mixture is stirred overnight at 25° C., filtered and the filtrate evaporated under vacuum to afford crude 1-chlorocarbonyloxy-2,4-dimethoxynaphthalene. This chloroformate is dissolved in 50 ml of dry tetrahydrofuran and a solution of 1.14 g of diethylamine in 10 ml of tetrahydrofuran added. After 4 hours at room temperature the reaction mixture is diluted with ethyl acetate and washed with dilute hydrochloric acid. The organic phase is dried over sodium sulfate and solvent removed under reduced pressure to yield 1-diethylcarbamoyloxy-2,4-dimethoxynaphthalene.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([CH3:7])[C:3](OC)=O.C[N+]1([O-])CC[O:21][CH2:20]C1.[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1>C1COCC1.C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:7][C:2]([C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)([CH3:1])[CH2:3][CH:20]=[O:21]
Reactant: C[N+]1([O-])CCOCC1
Reactant: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(CC=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 2-methyl-2-(4-nitrophenyl)propionate (5.32 g, 23.8 mmol) in THF (200 mL) at 0° C. was added a solution of 1M BH3 in THF (25.8 mL, 45.8 mmol). The reaction was stirred at RT overnight and was quenched with MeOH. THF was evaporated under reduced pressure and the residue was diluted in EtOAc and aqueous HCl (1M) was added. The mixture was extracted with EtOAc, the organic layer was dried over MgSO4 and evaporated under reduced pressure. Purification by flash chromatography using 40% EtOAc-hexane gave a yellow solid. To the yellow solid (2.08 g, 10.8 mmol) at 0° C. in CH2Cl2 was added NMO (1.9 g, 16.1 mmol), molecular sieves 4 Å and TPAP (76 mg, 0.2 mmol). The reaction was stirred for 1 h and filtered on a silica pad. Solvent was evaporated under reduced pressure, forming the crude aldehyde which was used as is. To a suspension of methoxymethyltriphenylphosphonium chloride (6.4 g, 18.6 mmol) in THF (150 mL) was added a solution of KHMDS 0.5 M in toluene (37 mL, 18.5 mmol). The mixture was stirred for 30 min and crude aldehyde was added. The reaction was stirred at RT for 1 h and quenched with H2O. The mixture was extracted with EtOAc, dried and evaporated under reduced pressure. Et2O was added and a precipitate formed, which was filtered on a silica pad and rinsed with 40% EtOAc-hexane. The solvent was removed and crude material was dissolved in CH2Cl2. A solution of TFA-H2O (1:1, 10 mL) was added and the reaction was stirred for 2 h at RT. Aqueous NaHCO3 was added until pH 7 and the mixture was extracted with CH2Cl2. The organic layer was dried, filtered and evaporated. Crude compound was purified by flash chromatography (40% EtOAc-hexane) to give the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C1COCC1.[C-]#[Si+].[C:19]([Cu])#[N:20]>O.CN1C(=O)CCC1>[Cl:11][C:4]1[N:3]=[C:2]([C:19]#[N:20])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: N#C[Cu]
Agent: [C-]#[Si+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 180 °C

Procedure:
2,6-dichloro-3-nitro-pyridine (2.5 g, 12.9 mmol) is taken up in a solvent mixture of THF and NMP (5:1, 13 mL), combined with two spatula tips of silicon carbide and CuCN (2.3 g, 26.0 mmol) and heated to 180° C. in the microwave reactor for 45 min. Then the solid obtained is suspended in H2O, extracted with ethyl acetate, washed with NaCl-sln., the organic phase is dried on MgSO4, the solvent is eliminated in vacuo and 6-chloro-3-nitro-pyridine-2-carbonitrile (HPLC-MS: tRet.=1.01 min, MS(M+H)+=182, method LCMSBAS1) is obtained.