Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:26][CH2:27][NH:28]C(=O)C(F)(F)F)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:28][CH2:27][CH2:26][N:18]([CH:15]1[CH2:16][CH2:17][N:13]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:14]1)[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24]
Reactant: COc1ccc2nccc(N3CCC(N(CCNC(=O)C(F)(F)F)C(=O)OC(C)(C)C)C3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc2nccc(N3CCC(N(CCN)C(=O)OC(C)(C)C)C3)c2n1
Reaction time: 12 h
Yield: 87.7 %

Procedure:
To a solution of 1,1-dimethylethyl {1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-pyrrolidinyl}{2-[(trifluoroacetyl)amino]ethyl}carbamate (1.8 g, 3.65 mmol) in MeOH/H2O (75 mL, 2:1) was added K2CO3 (2.52 g, 18.25 mmol). After 12 h at 25° C., the reaction was concentrated under reduced pressure and purified via column chromatography [silica, 5% MeOH in DCM (2% NH4OH)] affording the title compound (1.24 g, 88%) as an off-white solid: LC/MS (ES) m/e 388 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:3]=1[CH2:4][O:5]C1CCCCO1.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[F:1][C:2]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:3]=1[CH2:4][OH:5]
Reactant: Fc1cc(Oc2ccccc2)ccc1COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1ccc(Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
Mix under nitrogen atmosphere 2-(2-fluoro-4-phenoxy-benzyloxy)-tetrahydro-pyran (2.05 g, 6.8 mmol), methanol (60 mL) and p-toluenesulfonic acid monohydrate (260 mg, 1.35 mmol). Stir at ambient temperature for 16 h. Dilute with EtOAc. Wash with saturated aqueous NaHCO3. Separate the organic layer, dry over Na2SO4 and concentrate in vacuo to give the desired intermediate (1.41 g, 95%). MS (ES+) m/z: 201 (M−OH)+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([O:19][C:20]([NH:22][CH2:23][CH2:24][B-](F)(F)F)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.CC(=O)OCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:12]([O:19][C:20](=[O:21])[NH:22][CH2:23][CH2:24][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=C(NCC[B-](F)(F)F)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(CCNC(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 19.5 %

Procedure:
A flask was charged with 4-bromo-2-nitroaniline (505 mg), potassium (2-(((benzyloxy)carbonyl)amino)ethyl)trifluoroborate (745 mg), Pd(OAc)2 (25.3 mg), 2-(dicyclohexylphosphino)-2′,6′-dimethoxybiphenyl (94.6 mg) and Cs2CO3 (2.2 g) in dioxane/water (20 mL/2 mL). The reaction mixture was refluxed for 92 h, cooled down, diluted with EA and washed with water and brine. The aq. layers were extracted with EA, the combined org. layers were dried (MgSO4), filtered off and evaporated to dryness. The residue was purified by CC (Biotage, SNAP 25 g cartridge, solvent A: Hept; solvent B: EA; gradient in % B: 10 for 3CV, 10 to 30 over 3CV, 30 for 4CV, 30 to 50 over 3CV, 50 for 5CV) to afford 143 mg of red oil. LC-MS (B): tR=0.85 min; [M]+: 316.07.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:29][C@@H:24]1[C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][C:2]([C:41]5[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=5)=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(Cc3cc4c(=O)n([C@H]5CCOC[C@@H]5O)cnc4c4ccccc34)cn2)cn1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 1, 0.040 g, 0.095 mmol) in 1 mL of THF under an atmosphere of nitrogen was added cesium carbonate (0.19 mL, 1 N aqueous, 0.19 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.040 g, 0.19 mmol), and bis(tri-tert-butylphosphine)palladium(0) (10 mol %). The reaction was heated at 85° C. for 20 h, and additional 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.040 g, 0.19 mmol), and bis(tri-tert-butylphosphine)palladium(0) (10 mol %) were added. After 24 h, the reaction was cooled to rt, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and brine. The solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 467.53 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 8.87 (d, J=7.9 Hz, 1H), 8.35 (s, 1H), 8.23 (s, 1H), 7.80-7.78 (m, 2H), 7.72 (s, 2H), 7.66-7.55 (m, 2H), 7.22-7.19 (m, 1H), 7.08 (d, J=8.2 Hz, 1H), 4.80-4.73 (m, 1H), 4.28-4.15 (m, 1H), 4.08-4.04 (m, 1H), 3.85 (s, 3H), 3.61-3.51 (m, 1H), 3.34-3.29 (m, 1H), 2.28-2.18 (m, 1H), 1.99-1.95 (m, 1H).
Reaction SMILES: [O:1]1[C:3]2([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.[CH3:10][C:11]1[NH:15][C:14]([C:16]#[N:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][C:3]1([CH2:2][N:15]2[C:11]([CH3:10])=[CH:12][CH:13]=[C:14]2[C:16]#[N:17])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C1CCCC2(CC1)CO2
Reactant: Cc1ccc(C#N)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)n1CC1(O)CCCCCC1

Procedure:
1-Oxaspiro[2.6]nonane (2.5 g), 5-methyl-1H-pyrrole-2-carbonitrile (2.1 g) and Cs2CO3 (6.45 g) in N,N-dimethylformamide (15 mL) was heated at 120° C. in a Biotage Initiator microwave reactor for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and concentrated. The residue was purified by reverse phase chromatography, and was eluted with 30%-70% acetonitrile in 0.1% TFA water solution to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15]C(N)=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[H-].[Na+].O.[CH3:24][N:25]([CH:27]=[O:28])[CH3:26]>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][C:27]([N:25]4[CH2:26][C:20]5[C:2](=[CH:3][CH:4]=[CH:5][CH:19]=5)[CH2:24]4)=[O:28])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NC(=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1Cc2ccccc2C1
Reaction time: 3 h

Procedure:
To a mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetamide (2.56 g, 9.2 mmol) in DMF (40 ml) was chipped in sodium hydride (770 mg, 60% in oil, 20.1 mmol) at room temperature under N2. The mixture was heated to 65 C. for 3 hours. αα'-dibromoxylene (2.43 g, 9.2 mmol) was added and the resulting mixture was heated at 70 C. for 4 hours, then left standing overnight for 16 hours. The DMF mixture was poured into H2O (400 ml) and the organics were extracted into ethyl acetate (250 ml). The ethyl acetate solution was washed with brine and dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography over a silica gel column (SiO2, 45 gm; eluted with 1% CH3OH: 99% DCM). The product thus purified as a white solid weighed 1.73 g. Recrystallization from a small amount of ethanol yielded white crystals: 1.65 g, m.p. 184°-185° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:21][OH:22].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:21][OH:22])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ncc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(=NO)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.8 %

Procedure:
To a solution of 10.6 g of tert-butyl N-[2-(3,5-dichloropyridin-2-yl)-2-oxoethyl]carbamate and 4.8 g of hydroxylamine hydrochloride in 87 ml of ethanol, 6.1 g of pyridine was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 50 ml of water and extracted with ethyl acetate (100 ml×2), the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 40:60) as the eluent to obtain 10.1 g of the desired product as a pale yellow resinous substance.
Reaction SMILES: [C:1]1([CH:7]([N:11]([CH2:17][CH:18](OC)OC)[C:12](=O)[CH:13]([CH3:15])[CH3:14])C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:32]([O:34][CH3:35])=[O:33])=[CH:26][CH:25]=1.C(N(CC)CC)C.S(=O)(=O)(O)O>C(OC(=O)C)(=O)C.O>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:12]([CH:13]([CH3:14])[CH3:15])[N:11]3[CH:17]=[CH:18][C:2]4[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:7]=23)=[CH:28][CH:29]=1
Reactant: COC(=O)C#Cc1ccc(F)cc1
Reactant: COC(CN(C(=O)C(C)C)C(C(=O)O)c1ccccc1)OC
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(-c2ccc(F)cc2)c2c3ccccc3ccn2c1C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 2-phenyl-2-[N-(2,2-dimethoxyethyl)-2-methylpropanamido]acetic acid (32.1 g) and methyl 4-fluorophenylpropiolate (22.5 g) in acetic anhydride (120 ml) was treated with triethylamine (16 ml) and the resulting amber solution was stirred at room temperature under argon for 24 hours. The solution was then added, dropwise during 10 minutes, to concentrated sulphuric acid (200 ml), stirring and cooling by means of an icebath. The mixture was stirred for 30 minutes and then it was poured into iced water (2.5 liters), and extracted with dichloromethane (3×400 ml). The combined extracts were washed with water (250 ml) and with brine (250 ml), dried over magnesium sulphate and evaporated, to give a brown solid, which was recrystallised from methanol, to give methyl 1-(4-fluorophenyl)-3-isopropylpyrrolo[2,1-a]isoquinoline-2-carboxylate in the form of an off-white solid, m.p. 170°-173° C.
Reaction SMILES: [NH2:1]C1SC2C=C([N+]([O-])=O)C=CC=2N=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[C:14]([NH2:1])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Solvent: c1ccncc1
Solvent: O
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a suspension of 2-amino-6-nitrobenzothiazole (Sigma Aldrich, 2.93 g, 15 mmol) in pyridine (20 mL), benzoyl chloride (1.74 mL, 15 mmol) was added. After stirring over-night at r.t., additional benzoyl chloride (1.74 mL, 15 mmol) was added and the mixture was stirred at 60° C. After completion of the reaction, the mixture was poured into water (250 mL) and stirred overnight at r.t. Separation of the resulting precipitate yielded N-6-nitrobenzotihiazol-2-yl)benzamide (3.87 g, 12.9 mmol, 86%) as a yellow solid. LC/ESI-MS: m/z=300 [M+H]+; m/z=298 [M−H]−; Rt=3.93 min.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:26][C:27]1[C:28]([F:52])=[CH:29][C:30]([Cl:51])=[C:31]([CH:50]=1)[O:32][C:33]1[CH:47]=[CH:46][C:36]2[N:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[S:39][C:35]=2[C:34]=1[C:48]#[N:49]>O1CCCC1.C(OCC)(=O)C>[Cl:51][C:30]1[C:31]([O:32][C:33]2[CH:47]=[CH:46][C:36]3[N:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])[S:39][C:35]=3[C:34]=2[C:48]#[N:49])=[CH:50][C:27]([NH:26][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([C:3]3([C:1]#[N:2])[CH2:4][CH2:5]3)[CH:7]=2)=[C:28]([F:52])[CH:29]=1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1c(Oc2cc(NC(=O)c3cccc(C4(C#N)CC4)c3)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoic acid (74 mg, 0.330 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (35 μL, 0.408 mmol) and N,N-dimethylformamide (5 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(5-Amino-2-chloro-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (90 mg, 0.223 mmol) produced in Example 23(vi) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (7 mL) and saturated brine (7 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=20/80→80/20), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (105 mg, 83%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH2:9].[N:10]1([C:16]2[N:17]=[C:18]([CH2:23][C:24]([O-])=O)[NH:19][C:20](=[O:22])[CH:21]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[Na+].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(OCC)(=O)C>CO>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:24]([CH2:23][C:18]3[NH:19][C:20](=[O:22])[CH:21]=[C:16]([N:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[N:17]=3)=[N:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(F)cc1N
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3cc(F)ccc3[nH]2)[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.5 %

Procedure:
151 mg of 1,2-diamino-4-fluorobenzene are added to a solution of 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 8 ml of methanol. The resulting mixture is stirred at ambient temperature for 5 minutes and then 354 mg of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride hydrate are added. The resulting mixture is thus stirred for 30 minutes at ambient temperature. The reaction mixture is then concentrated to dryness under reduced pressure, and the residue is then taken up in 30 ml of acetic acid. The reaction mixture is brought to reflux for 1 hour, and then concentrated under reduced pressure. 30 ml of water are then added and a saturated aqueous solution of sodium bicarbonate is added until a pH in the region of 7 is obtained. 20 ml of ethyl acetate are then added and the resulting mixture is stirred for 1 hour. The precipitate formed is filtered off and subsequently purified by silica gel column chromatography, elution being carried out with a gradient of the eluent CH2Cl2/MeOH: 80/20 in dichloromethane of 0% to 100% in 25 minutes. 140 mg of 2-[(5-fluoro-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.C1(C)C=CC=CC=1.ClS([N:26]=[C:27]=[O:28])(=O)=O>O>[Cl:1][C:2]1[C:7]([NH:8][C:27]([NH2:26])=[O:28])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
370 Parts of 6-chloro-2,4-dinitroaniline are stirred for 4 hours at 80° C. in 2600 parts of toluene with 312 parts of chlorosulfonyl isocyanate. At 25° C., 360 parts of water are added to the resulting suspension of N-6-chloro-2,4-dinitrophenyl-N'-chlorosulfonyl urea without intermediate isolation, and the mixture is saponified at 60° C. within 4 hours to yield 6-chloro-2,4-dinitrophenyl urea. After diluting said mixture with water, it is neutralized with 33% sodium hydroxide solution, filtered while hot, and the product is thoroughly washed with hot toluene and water. After drying in vacuo, there are obtained 383 parts of 6-chloro-2,4-dinitrophenyl urea having a melting point of from 219° to 221° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>[Cu](I)I>[CH2:8]([C:6]1[C:5]([O:10][CH3:11])=[N:4][C:3]([CH3:12])=[C:2]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:7]=1)[CH3:9]
Reactant: c1c[nH]cn1
Reactant: CCc1cc(Br)c(C)nc1OC
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cc(-n2ccnc2)c(C)nc1OC
Temperature: 185 °C
Yield: 28.1 %

Procedure:
Into each of 2 microwave vials is added 3-bromo-5-ethyl-6-methoxy-2-methylpyridine (200 mg, 0.869 mmol), potassium carbonate (180 mg, 1.30 mmol), copper iodide (16 mg, 0.084 mmol), sodium hydroxide (84 mg, 2.10 mmol) and imidazole (59 mg, 0.869 mmol). The vials are flushed with N2 before anhydrous dimethylformamide (5.5 mL) is added and then sealed. Each reaction is heated in the CEM Discover microwave at 185° C. for 1 hr. The 2 reactions are combined diluted with water and extracted with 3 portions of dichloromethane. The combined dichloromethane layers are washed with 2 portions of 1 M aqueous sodium hydroxide, dried over magnesium sulfate and evaporated to give a dark oil. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:1). Fractions containing the product are combined. The solvent evaporated, and the residue is further purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1, increasing to 2:1). Clean fractions containing the product are combined and evaporated to give 3-ethyl-5-(imidazol-1-yl)-2-methoxy-6-methyl-pyridine (53 mg, 14% yield) as a yellow oil. MS: m/e=218 (M+H); 1H NMR (300 MHz, CDCl3, δ ppm): 7.54 (1H, s) 7.22 (1H, s), 7.21 (1H, s), 7.00 (1H, s), 3.98 (3H, s), 2.59 (2H, q), 2.25 (3H, s), 1.10 (3H, t).
Reaction SMILES: CC(OCC1CS[C@@H]2[C@H](NC(CCC[C@@H](N)C(O)=O)=O)C(=O)N2C=1C(O)=O)=O.[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>[Cl-].[Na+]>[CH:38]1[C:33]2[C:32](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][N:29]=1
Reactant: c1ccc2ncccc2c1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(=O)O)[C@H]2SC1
Agent: [Cl-]
Agent: [Na+]
Product: c1ccc2cnccc2c1

Procedure:
15 ml of the remaining reaction solution were diluted with a 5% sodium chloride solution to 30 ml (corresponds to 0.5% solution calculated as cephalosporin C). After adding 0.22 ml of quinoline to the solution, the mixture was adjusted to pH 3.0 and stirred at 5°-10° C. Very soon crystals separated out. The crystals were collected after an hour, washed with ice-water and with ethyl acetate and dried in vacuo. 226 mg of isoquinoline adduct of N-methylthioacetyl-cephalosporin C having 97% purity were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:11].[Se](=O)=[O:13]>O1CCOCC1>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH:11]=[O:13]
Reactant: Cc1nc2cnccc2n1C
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: Cn1c(C=O)nc2cnccc21
Temperature: 130 °C
Yield: 73 %

Procedure:
To a solution of 1,2-dimethyl-1H-imidazo[4,5-c]pyridine (500 mg, 3.40 mmol) in dry 1,4-dioxane (7.5 mL) was addedhttp://newsearchch.chemexper.com/cheminfo/servlet/org.dbcreator.MainServlet?sort=%3E%7Eentry.intValue&query=structure._structureID%3D4635571&target=entry&action=PowerSearch&onclick=1&from=0&history=off&forGroupNames=&style=&realQuery=rn.value%3D%22CF3COOH%22+elsor+entry.catalogID%3D%22CF3COOH%22+elsor+iupac.value%3D%22CF3COOH%22+elsor+mf.value%3D%22CF3COOH%22+elsor+%28iupac.value%3D%7E%22CF3COOH%22+or+catalog.description%3D%7E%22CF3COOH%22%29&format=ccd&searchTemplate=rn.value%3D%3F+elsor+entry.catalogID%3D%3 selenium dioxide (665 mg, 5.10 mmol). The mixture heated by microwave at 130° C. for 5 min. Then the mixture was filtered and concentrated to give the crude product, which was purified by column chromatography (silica gel, petroleum ether:DCM 10:1 to 1:1) to give the title compound (400 mg, yield 28%). LC-MS (ESI) m/z: 162 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.61 (s, 3H), 5.91 (s, 1H), 7.67-7.70 (d, J=5.6 Hz, 1H), 8.39-8.41 (d, J=5.6 Hz, 1H), 8.93 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][C:9]#N)=[CH:5][CH:4]=1.O.CC(O)=[O:16]>[Ni].N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC#N)cc1
Reactant: CC(=O)O
Agent: [Ni]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C=CC=O)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
To 2 g (12.6 mmol) 4-methoxycinnamonitrile in 10:10:20 ml H2O:HOAc:pyridine was added 5 g (47 mmol) NaH2PO2 (hypophosphite) followed by 2 g RaNi. After stirring 3 hours at 50° C., the reaction mixture was filtered, extracted with CH2Cl2, washed with dilute HCl, washed with H2O and evaporated to give 0.7 g (35% yield) 4-methoxycinnamaldehyde, a yellow solid, m.p. 47° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.Cl[C:25]([O:27][CH2:28][CH:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26]>ClCCl.C(OCC)C>[CH:40]1[C:41]2[CH:29]([CH2:28][O:27][C:25]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:26])[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]=2[CH:37]=[CH:38][CH:39]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (19.23 g, 0.104 mol) and N,N-diisopropylethylamine (27.3 mL, 0.157 mol) in dichloromethane (500 mL) was added 9-fluorenylmethyl chloroformate (27 g, 0.104 mol). The reaction mixture was stirred at room temperature under nitrogen for 4 hours, and then washed with 1 M hydrochloric acid (3×300 mL), water (300 mL) and brine (300 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a pale yellow solid. The solid was slurried in dichloromethane (75 mL), the slurry was diluted with diethyl ether (300 mL) and the resulting white suspension stirred overnight. Filtration afforded the title compound (34.64 g, 82%) as a white solid, m.p. 141-142° C.