Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)[CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[N:9][CH2:10][CH3:11].[N+:13]1([O-])[CH:18]=[CH:17][C:16]([C:19](O)=O)=[CH:15][CH:14]=1.O.ON1[C:29]2[CH:30]=C[CH:32]=[CH:33][C:28]=2N=N1>>[NH:13]1[CH2:18][CH2:17][C:16](=[C:19]2[C:30]3[CH:29]=[CH:28][CH:33]=[CH:32][C:4]=3[CH2:5][CH2:6][N:7]3[CH:11]=[CH:10][N:9]=[C:8]23)[CH2:15][CH2:14]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc[n+]([O-])cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Product: c1ccc2c(c1)CCn1ccnc1C2=C1CCNCC1

Procedure:
6,11-dihydro-11-(4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine (C) was prepared as described in Example 4. The Aldrich Chemical Company supplies 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, pyridine-4-carboxylic acid N-oxide, and 1-hydroxybenzotriazole hydrate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].[C:33]([O:37][C:38](=[O:41])[CH2:39]Br)([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:39][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:41])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 0.40 g (0.94 mmol) of the product of Example 37 in 10 mL of DMF was added 0.047 g (1.171 mmol) of a 60% suspension of sodium hydride in minena oil. The resulting mixture was stirred at room temperature for 0.5 h and then 0.277 mL (1.873 mmol) of t-butylbromoacetate was added in one portion. Th reaction mixture was stirred for an additional 18 h and then diluted with ether, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether-hexanes to provide 0.423 g (83%) of the desired product as a white solid. Electrospray Mass Spec: 524.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20](C(C)=C)[C:19]3=[O:30])[CH2:11][CH2:10]2)=[C:4]([N+:31]([O-:33])=[O:32])[CH:3]=1.CC1C=CC=CC=1.Cl>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:30])[CH2:13][CH2:14]2)=[C:4]([N+:31]([O-:33])=[O:32])[CH:3]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCC(Nc3ccc(Cl)cc3[N+](=O)[O-])CC2)c2ccccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1
Yield: 75.5 %

Procedure:
A solution of 98.5 parts of 1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one in 360 parts of methylbenzene is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride. After boiling for a while, an oil precipitates. The supernatant phase is decanted and the residual oil is suspended in water. The suspension is alkalized with a concentrated ammonium hydroxide solution. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 68 parts (75.5%) of 1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C>C(#N)C.ClCCl>[C:32]([NH:36][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[CH3:1])([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1ncccc1C(=O)O
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ncccc1C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 12-L, three-neck, round-bottom flask equipped with a mechanical stirrer, a thermocouple, and a nitrogen inlet gas adapter is charged with 2-methyl nicotinic acid (302 g, 2.2 mol), EDCI (464 g, 2.4 mol), HOBt (327.3 g, 2.4 mol, 1.1 equiv) and 4.5 L of anhydrous acetonitrile. The mixture is stirred for 45 minutes at room temperature to dissolve most of the solids and is then cooled to 5° C. using an ice-water bath. A mixture of t-butylamine (242 mL, 2.5 mol) and Hunig's base (402 mL, 2.5 mol) in 500 mL of anhydrous acetonitrile and 500 mL of anhydrous dichloromethane is added slowly over 45 minutes, maintaining the temperature below 10° C. The mixture is stirred for 15 hours at room temperature under nitrogen. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate (3.0 L) then washed with saturated ammonium chloride solution (2.0 L). The organic-phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification of the resultant crude residue by silica gel flash column chromatography followed by trituration with 5% ethyl acetate/heptane gives the title compound.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:18][CH:17]=2)=[C:9]([CH2:11][C:12]#[N:13])[CH:10]=1.S(=O)(=O)(O)O.O1CCCC1>O>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[O:27][C:28]=3[CH3:29])=[CH:20][CH:21]=2)=[C:9]([CH2:11][C:12]#[N:13])[CH:10]=1
Reactant: COCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CC#N)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(O)cc2CC#N)cc1
Yield: 68.1 %

Procedure:
A mixture of 2-[5-methoxymethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile (1.83 g), 10% sulfuric acid (5 mL) and tetrahydrofuran (50 mL) was heated under reflux for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (1.13 g, 68%) of 2-[5-hydroxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 185-186° C.
Reaction SMILES: [Li].[Cl:2][C:3]1([CH3:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.C1C[O:12]CC1>>[Cl:2][C:3]1([CH3:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:8][C:3]1([OH:12])[CH2:7][CH2:6][CH2:5][CH2:4]1.[ClH:2]
Reactant: C1CCOC1
Agent: CC1(Cl)CCCC1
Agent: [Li]
Product: CC1(O)CCCC1
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To lithium sand (0.44 g, 63.0 mmol) in THF (100 mL) at 0° C. under argon was added 4,41-di-tert-butylbiphenyl (13.27 g, 51.0 mmol) and the resulting mixture was stirred at 0° C. overnight. The mixture was then cooled to −78° C. and 1-chloro-1-methylcyclopentane (3.0 g, 25.3 mmol) in THF (25 mL) was added. [1-Chloro-1-methylcyclopentane, a clear oil with b.p. 87-88° C./15T was obtained by the chlorination of 1-methylcyclopentanol with HCl gas.] This mixture was stirred for 15 min and the compound of Example g (5.34 g, 25.3 mmol) was added. The resulting solution was stirred at −78° C. for 1 h before being poured into water (250 mL). The aq layer was extracted three times with ether, and the combined extracts were dried (MgSO4) and concentrated to yield 2-[2-fluoro-6-(1-methyl-cyclopentyl)phenyl]-4,5-dihydro-4,4-dimethyloxazole, as a clear oil in 40% yield. This oxazoline was carried through Steps 1-4 of Example 90. The resulting final product was recrystallized from ether/hexanes and obtained as a white solid. m.p. 116-117° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 64. LC-MS Method 1 tR=1.29 min, m/z=431 (M+1); 1H NMR (CDCl3) 8.71 (d, 1H, J=6 Hz), 7.78 (d, 1H, J=6 Hz), 7.7 (s, 1H), 7.49 (t, 2H, J=7, 7 Hz), 7.27-7.24 (m, 2H), 7.17 (m, 2H), 7.09-7.02 (aq, 2H, J=9, 17 Hz), 5.73 (q, 1H, J=7, 14 Hz), 4.27 (t, 1H, J=6, 6 Hz), 3.60 (t, 1H, J=6, 6 Hz), 3.09-3.03 (m, 1H), 2.95 (s, 3H), 2.41-2.25 (m, 3H), 2.06-1.90 (m, 2H) 1.73-1.64 (m, 1H), 1.58 (d, 3H, J=7 Hz), 1.40-1.33 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[N:17]1[C:26](=[O:27])[CH:25]2[CH:20]([CH:21]3[CH2:28][CH:24]2[CH:23]=[CH:22]3)[C:18]1=[O:19].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][N:17]1[C:26](=[O:27])[CH:25]2[CH:20]([CH:21]3[CH2:28][CH:24]2[CH:23]=[CH:22]3)[C:18]1=[O:19])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1C2C3C=CC(C3)C2C(=O)N1OS(=O)(=O)C(F)(F)F
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a solution of trifluoromethanesulfonic anhydride (6.5 g, 23 mmole) in methylene chloride (20 ml), a solution of N-hydroxy-bicyclo[2,2,1]-hept-5-ene-2,3-dicarboximide (3.6 g, 20 mmole) and pyridine (1.6 g) in methylene chloride (10 ml) was added dropwise at 0°-5° C. and continued to stir for 15 minutes at the same temperature. The reaction mixture was washed with H2O (20 ml×3), dried over anhydrous MgSO4 and evaporated. The residue was recrystallized from ethanol to give 6.1 g of N-trifluoromethanesulfonyloxy-bicyclo-[2,2,1]-hept-5-ene-2,3-dicarboximide as white needles. m.p. 89°-90° C.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)(Cl)[Cl:41]>C(Cl)Cl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27]([Cl:41])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=C(C(=O)Cl)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred solution of anhydrous methylene chloride (200 ml) containing 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino acetic acid (syn-isomer) (11.35 g; 0.0256 mole) and triethylamine (3.61 ml; 0.0256 mole), was cooled at 0° C. and phosphorus pentachloride (5.6 g; 0.027 mole) was added portionwise. After 15 minutes of stirring at 0° C. and 1 hour at room temperature, the mixture was evaporated under reduced pressure, taken up with anhydrous benzene, evaporated again in order to remove any trace of phosphorus oxychloride. This treatment was repeated twice (2×50 ml). The residue was suspended in 50 ml of anhydrous acetone; triethylamine hydrochloride was then removed by filtration. The acetone solution of 2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetyl chloride thus obtained was dropped into a vigorously stirred ice-cooled solution of 7-amino-3-[(8-carboxy-6-tetrazolo[1,5-b]pyridazinyl)-thiomethyl]-3-cephem-4-carboxylic acid (10 g; 0.0232 mole) NaHCO3 (15 g) in a mixture of water and acetone (500 ml; 250 ml). The mixture was stirred for 30 minutes at 0°-5° C. and then for 90 minutes at room temperature, the undissolved matter was filtered off, the acetone was eliminated by evaporation under vacuum. The aqueous phase was brought to pH 2 with 8% HCl and extracted with ethyl acetate (3×400 ml), washed with aqueous sodium chloride, dried (Na2SO4) and evaporated to dryness. The residue was stirred with diethyl ether; after 20 minutes of stirring the white solid was filtered, washed with ether and dried thus giving 3-[(8-carboxy-6-tetrazolo[1,5-b]pyridazinyl)-thiomethyl]-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid. The above mentioned compound was added portionwise to a stirred hot (55° C.) solution of 50% formic acid (140 ml). Stirring and heating at the same temperature was maintained for 30 minutes and then the solid was filtered from the cooled mixture. The filtrate was evaporated to dryness under vacuum, leaving a residue. After complete removal of water and formic acid, followed by trituration with water, a solid was obtained. The crude product was crystallized from 50% ethanol to give 9.1 g (60%) of the title compound, which decomposed at 255° C.
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([S:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:2]3[N:21]=[C:5]4[C:6]([S:10][C:11]5[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: CC(=O)Nc1ccc(Sc2cccn3nc(Cl)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(=O)Nc1ccc(Sc2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)cc1

Procedure:
A solution of 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.47 g, 2.00 mmol) in dioxane (6.0 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.256 g, 0.28 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.324 g, 0.56 mmol), N,N-disopropylethylamine (0.52 g, 4.00 mmol), and acetamidothiophenol (0.37 g, 2.20 mmol) under nitrogen. The mixture was degassed with nitrogen for 3 minutes, and then heated to 100° C. for 14 hours. The reaction was cooled to room temperature, filtered through diatomaceous earth, washed with dichloromethane, and concentrated. The residue was diluted with dichloromethane, washed with brine, dried over sodium sulfate, and concentrated. The crude was purified by flash chromatography (silica gel hexane to 5% methanol in dichloromethane) to give N-[4-(2-chloro-[1,2,4]triazolo[1,5-a]pyridine-8-ylsulfanyl)-phenyl]acetamide (0.51 g, 80%). MP=148-150° C. MS=319 (MH)+. 281b) 4-{4-[8-(4-Acetylamino-phenylsulfanyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from N-[4-(2-chloro-[1,2,4]triazolo[1,5-a]pyridine-8-ylsulfanyl)-phenyl]acetamide and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.023 g, 10%). MP=226-228° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.2 (s, 1H), 9.69 (s, 1H), 8.62 (d, 1H), 7.72 (m, 2H), 7.55 (m, 2H), 7.49 (m, 2H), 7.12 (m, 2H), 6.91 (m, 1H), 4.18 (bs, 2H), 2.78 (bs, 2H), 2.58 (m, 1H), 2.04 (s, 3H), 1.66 (m, 2H), 1.51 (m, 2H), 1.42 (s, 9H). MS=559 (MH)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[O:11][CH2:12][CH2:13][NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](N[C:22]1[NH:27][C:26](=[O:28])[C:25]([O:29][CH3:30])=[CH:24][N:23]=1)([O-])=O>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[O:11][CH2:12][CH2:13][NH:14][C:22]2[NH:27][C:26](=[O:28])[C:25]([O:29][CH3:30])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCOc1cccc(CN2CCCCC2)c1
Reactant: COc1cnc(N[N+](=O)[O-])[nH]c1=O
Solvent: c1ccncc1
Product: COc1cnc(NCCOc2cccc(CN3CCCCC3)c2)[nH]c1=O

Procedure:
2-[3-(Piperidinomethyl)phenoxy]ethylamine * (1.38 g) and 2-nitroamino-5-methoxypyrimidin-4-one(1.00 g) were stirred under reflux, for 19 hours, in pyridine (15 ml). The reaction mixture was worked-up in a manner analogous to that of Example 5 to give the title compound which was converted to 2-[2-[3-(piperidinomethyl)phenoxy]-ethylamino]-5-methoxypyrimidin-4-one maleate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[CH:9]12[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:13]([CH2:14][CH2:15]1)[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:10]2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 22 h
Yield: 86.6 %

Procedure:
A mixture of 8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane (238 mg, 1.12 mmol), benzyl chloroformate (160 μL, 1.12 mmol) and triethylamine (280 μL, 2.0 mmol) in DCM (20 mL) was stirred at room temperature for 22 h. The reaction mixture was diluted with DCM (20 mL) and washed with water (25 mL). The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo to give the title compound (336 mg, 87%) as a clear oil. δH (DMSO-d6) 7.45-7.28 (5H, m), 5.17-5.03 (2H, m), 4.18-4.06 (2H, m), 3.79-3.69 (2H, m), 3.10-2.90 (2H, m), 1.85-1.72 (2H, m), 1.60-1.49 (2H, m), 1.41 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[O:21]([C:28]([NH:30][C:31]1[CH:32]=[C:33]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[O:34][CH:35]1[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]1)=O)C1C=CC=CC=1.O.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH:16]1([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:19]=[CH:20][C:2]([NH:1][C:28]([NH:30][C:31]4[CH:32]=[C:33]([CH:46]=[C:47]([C:49]([F:51])([F:52])[F:50])[CH:48]=4)[O:34][CH:35]4[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]4)=[O:21])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(NC(=O)Oc3ccccc3)cc(C(F)(F)F)c2)C1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(NC(=O)Nc3ccc(Oc4ccnc(NC(=O)C5CC5)c4)cc3)cc(C(F)(F)F)c2)C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 69.3 %

Procedure:
Dissolve N-[4-(4-aminophenoxy)-2-pyridyl]cyclopropanecarboxamide (186 mg, 0.69 mmol), tert-butyl 3-[3-(phenoxycarbonylamino)-5-(trifluoromethyl)phenoxy]azetidine-1-carboxylate (312 mg, 0.69 mmol) and DMAP (17 mg, 0.14 mmol) in DMF (10 mL), stir at 100° C. for 16 hrs. Cool the reaction, pour the mixture to water (50 mL), adjust pH=7 with saturated NaHCO3 solution, extract with EtOAc (15 mL×3). Combine the organic layers, wash with brine (100 mL), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the target compound (300 mg, 69%). MS: (M+1): 628.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CC=CC=1.[CH3:23][O:24][C:25](Cl)=[O:26]>ClC(Cl)C.ClCCl>[CH3:23][O:24][C:25](=[O:26])[NH:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: COC(=O)Cl
Reactant: Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Temperature: 60 °C
Yield: 86 %

Procedure:
To a stirred solution of 0.20 g of (3-amino-5-bromo-phenyl)-pyridin-3-yl-methanone (0.72 mmol) in 5 mL of dichloroethane was added 0.58 mL of pyridine and 0.55 mL of methylchloroformate, and the mixture was heated to 60° C. for 20 minutes. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate, dried over NaSO4 and the volatiles were removed under reduced pressure to give 208 mg (86% yield) of [3-bromo-5-(pyridine-3-carbonyl)-phenyl]-carbamic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[Br:8][C:4]1[N:3]=[C:2]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])[CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1cccc(Br)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
A mixture of 2,6-dibromopyridine (2.07 g, 8.7 mmol), 2-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)benzonitrile (prepared as described in Tetrahedron (2001), 57(49), 9813-9816, 3.00 g, 13 mmol) and potassium phosphate (3.71 g, 17 mmol) in DMF (40 mL) was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (303 mg, 0.26 mmol) was added, the mixture was degassed as before, and was then stirred at 80° C. under nitrogen overnight. The mixture was partitioned between water and ethyl acetate, and the resulting aqueous layer was washed with ethyl acetate (2×100 mL). The combined organic layers were washed with water (1×100 mL) and saturated sodium chloride solution (1×100 mL), then were dried over magnesium sulfate and concentrated in vacuo. The residual material was purified by flash chromatography on silica gel, eluting with 50% ethyl acetate in isohexane, affording 2-(6-bromopyridin-2-yl)benzonitrile as a solid (680 mg, 30%). δH (400 MHz, CDCl3) 7.51-7.57 (2H, m), 7.68-7.73 (2H, m), 7.80 (2H, d, J 7.7), 7.91 (1H, dd, J 0.7 and 7.7).