Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[C:35]([OH:36])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][CH2:47][O:48][CH3:49].[I-].[K+]>CN(C)C=O.O>[F:38][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[C:35]([O:36][CH2:46][CH2:47][O:48][CH3:49])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: COCCBr
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4c(O)cccc4Cl)C3)cs2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cccc(Cl)c1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 80 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (39 mg) and potassium carbonate (47 mg) in N,N-dimethylformamide (5 ml) are added, at room temperature, 1-bromo-2-methoxyethane (38 mg) and potassium iodide (1.1 mg). The reaction mixture is stirred at 80° C. for 3 h. Then the mixture is admixed with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-chloro-6-(2-methoxyethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone (17 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:4]3[C:5](=[CH:13][N:14]([C@@H:16]4[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@:17]4([CH3:25])[OH:18])[N:15]=2)[CH:6]=[CH:7][C:8]=3[C:9](=[O:12])[NH:10][N:11]=1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CN=C1>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:4]3[C:5](=[CH:13][N:14]([C@@H:16]4[O:22][C@H:21]([CH2:23][O:24][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@@H:19]([OH:20])[C@@:17]4([CH3:25])[OH:18])[N:15]=2)[CH:6]=[CH:7][C:8]=3[C:9](=[O:12])[NH:10][N:11]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2ccc3c(=O)[nH]nc(N)c(n1)c23
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc3ccc4c(=O)[nH]nc(N)c(n2)c34)[C@](C)(O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
A mixture of 4-amino-2-(2-C-methyl-β-D-ribofuranosyl)-2,6-dihydro-7H-2,3,5,6-tetraazabenzo[cd]azulene-7-one (65 mg, 0.19 mmol) in DMF, tert-butyldimethylsilyl chloride (70 mg, 0.45 mmol) and imidazole (61 mg, 0.90 mmol) was stirred overnight at room temperature and then concentrated in vacuo. The oily residue was dissolved in CH2Cl2 (20 mL), washed with aq. HCl (0.1 N), sat. aq. NaHCO3, water, brine and dried (Na2SO4). The evaporated residue was purified on silica gel with hexanes/EtOAc (1/1)+0.5% Et3N and EtOAc+0.5% Et3N to yield the target compound 16.1 as colorless oil (38 mg, 44%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][N:12]=1>CS(C)=O>[CH3:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]([CH3:4])[N:12]=1
Reactant: C[S+](C)(C)=O
Reactant: COc1ncc([N+](=O)[O-])cc1C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1nc(C)c([N+](=O)[O-])cc1C
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Dimethyl sulfoxide (35 mL) was added to a dry round-bottomed flask containing NaH (1.82 g, 45.5 mmol, 60% in mineral oil). The resulting suspension was heated at 70° C. for 35 min during which time the suspension became a solution. The reaction mixture was cooled to room temperature, trimethylsulfoxonium iodide (10.0 g, 45.5 mmol) was added, and the mixture was stirred at room temperature for 30 min. 2-Methoxy-3-methyl-5-nitropyridine (4.50 g, 26.80 mmol) was added and the resulting dark red solution was stirred at room temperature for 30 min, at which time TLC showed complete consumption of starting material. The reaction mixture was transferred to a separatory funnel containing water (30 mL), and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by MPLC (silica gel, 20% ethyl acetate in hexanes) to afford 2-methoxy-3,6-dimethyl-5-nitropyridine (2.00 g, 41% yield) as a colorless solid identical to that prepared by the previous method: mp 85.5-86.2° C.; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 4.02 (s, 3H), 2.77 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:17]=[CH:18][C:19]4[N:20]([C:22]([CH:25]5[CH2:29][CH2:28][NH:27][CH2:26]5)=[N:23][N:24]=4)[CH:21]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:17]=[CH:18][C:19]4[N:20]([C:22]([CH:25]5[CH2:29][CH2:28][N:27]([C:30](=[O:32])[CH3:31])[CH2:26]5)=[N:23][N:24]=4)[CH:21]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3occn3c2-c2ccc3nnc(C4CCNC4)n3c2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCC(c2nnc3ccc(-c4c(-c5ccc(F)cc5)nc5occn45)cn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
To a suspension of 6-(4-fluorophenyl)-5-(3-(pyrrolidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)imidazo[2,1-b]oxazole (0.100 g, 0.26 mmol; Example #M.1.1.3) in DCM (5 mL) was added TEA (0.04 mL, 0.26 mmol) and acetyl chloride (0.02 mL, 0.26 mmol). The reaction mixture was stirred at ambient temperature for about 16 h. The crude reaction mixture was purified by flash chromatography (silica gel; DCM/MeOH gradient from 99:1 to 90:10) to afford the title compound (0.02 g, 17%). LC/MS (Table 1, Method a) Rt=1.79 min; MS m/z: 431.1 (M+H)+.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].Br[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][CH2:29][CH2:28]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH2:29][CH2:28]3)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: BrCCc1ccc2c(c1)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc3c(c2)CCC3)C1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.6 g--see Preparation 8), 5-(2-bromoethyl)indane (0.49 g--see Preparation 14), anhydrous potassium carbonate (0.6 g) and acetonitrile (20 ml) was heated under reflux for 1.25 hours. The mixture was partitioned between 10% aqueous potassium carbonate (10 ml) and dichloromethane (50 ml), the layers were separated and the aqueous layer extracted with dichloromethane (3×100 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.29 g.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:6].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH:6][C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H](NC(=O)Oc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
L-aspartic acid dimethyl ester hydrochloride (2.0 g, 10 mmol) was dissolved in dichloromethane (30 ml), phenyl chloroformate (1.3 mL, 11 mmol) and N,N-diisopropylethylamine (4.4 mL, 25 mmol) were added at 0° C., and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].O.O.O.C([O-])(=O)C.[Na+].O.[NH2:23][NH2:24]>C(O)(=O)C>[F:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[C:4]2[C:3]=1[C:8](=[O:7])[N:23]=[N:24][C:5]2=[O:6]
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1N=NC(=O)c2c(F)ccc(F)c21
Yield: 99.2 %

Procedure:
3,6-Difluorophthalic anhydride (10 g, 54 mmol) was added to a mixture of sodium acetate trihydrate (10 g, 73 mmol) and hydrazine hydrate (5 ml, 156 mmol) in 40% aqueous acetic acid. The reaction was heated under reflux conditions for 16 h and the reaction was filtered to give the title-compound as a white solid (10.5 g, 98%), 1H NMR (250 MHz, d6-DMSO) δ 8.01 (2H, t, J=9 Hz), 11.50-11.80 (2H, br s).
Reaction SMILES: [N+:1]1([O-:10])[O:5][N:4]=[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=12.[N+]([CH2:14][CH3:15])([O-])=O.C(NCC)C>O1CCCC1>[CH3:14][C:15]1[N:4]([OH:5])[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[N+:1]=1[O-:10]
Reactant: CC[N+](=O)[O-]
Reactant: [O-][n+]1onc2ccccc21
Solvent: CCNCC
Solvent: C1CCOC1
Product: Cc1n(O)c2ccccc2[n+]1[O-]
Reaction time: 1 h
Yield: 58.5 %

Procedure:
In the typical procedure, 0.1 mole of benzofurazan 1-oxide and 0.12 mole of nitroethane is dissolved at 100 ml. of tetrahydrofuran. To this mixture there is added at room temperature, 0.12 mole of diethylamine over a period of 0.5 hour. An instantaneous exothermic reaction is observed (40° C.) and within one hour, the product crystallizes from the solution. The solution is allowed to stand overnight at room temperature and filtered to yield 9.6 grams of 2-methyl-1-hydroxy-1-H-benzimidazole 3-oxide (Table III, Example H-77). The product can be recrystallized from methanol.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1([C:23]([S:26]CC1C=CC(OC)=CC=1)=[N:24][CH3:25])[N:15]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=[CH:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1([N:15]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=[CH:16]1)[C:23](=[S:26])[NH:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN=C(SCc1ccc(OC)cc1)C1(n2cnc([N+](=O)[O-])c2)CCCCC1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=S)C1(n2cnc([N+](=O)[O-])c2)CCCCC1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
6.18 g (12.4 mmol) of the 2-benzyloxy-1-((4-methoxybenzylthio)(methylimino)methyl)-1-(4-nitroimidazol-1-yl)cyclohexane prepared in the Preparative Example 14 was dissolved in 28 ml of trifluoroacetic acid under cooling with ice, followed by the addition of 5 ml of anisole. The obtained mixture was stirred at 0° C. for 10 minutes to give a dark-brown solution, which was pored onto a mixture comprising a saturated aqueous solution of sodium hydrogencarbonate and ice. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate, and concentrated in a vacuum. The residue (8.02 g) was purified by silica gel column chromatography [solvent: dichloromethane/acetone (40:1)], and recrystallized from dichloromethane/diisopropyl ether to give 3.14 g of the title compound as a colorless crystal (yield: 67%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:40][CH:39]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[CH2:38]3)=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1.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>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:31]4[CH:36]=[CH:35][C:34]([N:37]5[CH2:40][CH:39]([N:41]6[CH2:42][CH2:43][O:44][CH2:45][CH2:46]6)[CH2:38]5)=[CH:33][CH:32]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CC1(C)OB(c2ccc(N3CC(N4CCOCC4)C3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1nc(-c2ccc(N3CC(N4CCOCC4)C3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Yield: 3.6 %

Procedure:
To a 2-5 ml microwave vial, combined (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (85 mg, 0.23 mmol), 4-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-3-yl)morpholine (100.15 mg, 0.29 mmol), tetrakis(triphenylphosphine)palladium (26.89 mg, 0.02 mmol), 1M Sodium carbonate soln in water (0.7 ml) in dioxane (2.3 mL) and blown down with nitrogen. The reaction was irradiated for 20 mins at 150 C. The reaction was diluted with water, extracted with DCM, combined organics, dried (Na2SO4), filtered, concentrated. Residues were purified by silica gel column chromatography to yield the title compound (4.2 mg, 3.6%) as a free base.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16](C(=O)C)[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH:2]=1.[BH4-].[Na+].[C:25](O)(=[O:27])[CH3:26]>C(O)C>[CH3:26][CH:25]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:9]2[N:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[CH:15][CH:16]=1)[OH:27]
Reactant: CC(=O)O
Reactant: CC(=O)c1cccc(Nc2nccc(-c3cccnc3)n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reaction time: 3 h

Procedure:
A 1.45 g portion of 1-[3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]ethanone was dissolved with stirring in 220 ml of ethanol. A 125 mg portion of sodium borohydride was added and stirring continued for 3 hours. A 63 mg portion of sodium borohydride was added and stirring continued overnight. A 2 ml portion of glacial acetic acid was added and the mixture evaporated. The solid was triturated with water, dried and recrystallized from 30 ml of ethanol giving 710 mg of the desired product, mp 145°-147° C.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH:6]=[N:7][C:8]2[CH:13]=[CH:12][C:11]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Si]([C:24]#[N:25])(C)C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14](=[O:16])(=[O:17])[NH2:15])=[CH:10][CH:9]=2)[C:24]#[N:25])=[CH:18][CH:19]=1
Reactant: Cc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: Cc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-methylbenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a white powder (yield 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH:16]([C:17](OC)=[O:18])[O:15][NH:14][C:13]1=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH3:23]>>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH:16]([C:17](=[O:18])[NH2:23])[O:15][NH:14][C:13]1=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1ONC(=O)C1NC(=O)OCc1ccccc1
Reactant: N
Solvent: O
Product: NC(=O)C1ONC(=O)C1NC(=O)OCc1ccccc1
Reaction time: 0.33 h

Procedure:
In 2.4 ml of concentrated ammonia water was dissolved 150 mg of 4-benzyloxycarbonylamino-5-methoxycarbonyl-3-isoxazolidinone (mixture of 4,5-cis compound and -trans compound). The solution was left standing at room temperature for 20 minutes, which was concentrated to dryness under reduced pressure. Ether was added to the concentrate to give 138 mg of 4-benzyloxycarbonylamino-5-carbamoyl-3-isoxazolidinone as crystals.
Reaction SMILES: C([C:5]1([NH:31]C(=O)[O-])[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[C:14]([Br:29])[C:13]2=[O:30])=[CH:7][CH2:6]1)(C)(C)C.O1CCOCC1>Cl.C(OCC)C>[NH2:31][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[C:14]([Br:29])[C:13]2=[O:30])=[CH:9][CH:10]=1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1CC1=CCC(NC(=O)[O-])(C(C)(C)C)C=C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
1-tert-butyl-4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}phenylcarbamate (Step 1) (6.14 g, 11.47 mmol) was suspended in 4N HCl in dioxane (5.74 mL, 22.94 mmol). The reaction mixture was stirred at room temperature for 1 hour then diluted with diethyl ether. The precipitate was collected by filtration and washed with diethyl ether (3×30 mL) to afford a tan solid (3.45 g, 69%). 1H NMR (400 MHz, DMF-d6) δ 7.64 (app dt, J=6.58, 8.59 Hz, 1H), 7.31 (ddd, J=2.55, 9.53, 10.61 Hz, 1H), 7.29-7.12 (m, 5H), 6.56 (s, 1H), 5.28 (s, 2H), 5.27 (s, 2H), 2.28 (s, 3H) ES-HRMS m/z 435.0516 (M+H calcd for C20H18BrF2N2O2 requires 435.0514).
Reaction SMILES: [CH2:1]([C:8]1[C:20](=[O:21])[N:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[CH:44][CH:45]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:41]=[N:42][C:43]([NH:46][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:20](=[O:21])[N:19]([CH:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[C:11]=4[N:12]=3)=[CH:44][CH:45]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CS(=O)c1ncc2cc(Cc3ccccc3)c(=O)n(C3CCCC3)c2n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(Cc5ccccc5)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Yield: 19.9 %

Procedure:
6-Benzyl-8-cyclopentyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.64 g, 1.74 mmol) and 4(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.87 g, 2.96 mmol) in toluene (10 ml) were heated to 95° C. for 28 hours. The reaction mixture was allowed to cool then chromatographed on silica gel using a gradient of 20 to 50% ethyl acetate in hexane. The product-containing fractions were evaporated and the residue was triturated with acetonitrile to give a solid. This solid was collected by filtration and dried in vacuo to provide 4-[6-(6-benzyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.201 g, 19.8%). MS (APCI) M++1: Calc'd, 582.31, Found, 582.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([Mg]Br)[CH:7]=[CH:6]2.[Cl-].[Zn+2:16].[Cl-]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([Zn:16][C:8]1[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=1)[CH:7]=[CH:6]2
Reactant: [Zn+2]
Reactant: COc1ccc2cc([Mg]Br)ccc2c1
Agent: [Cl-]
Solvent: c1ccccc1
Product: COc1ccc2cc([Zn]c3ccc4cc(OC)ccc4c3)ccc2c1

Procedure:
The resulting solution of 6-methoxy-2-naphthylmagnesium bromide in 50 ml. of benzene under nitrogen is added 3.14 g. of anhydrous zinc chloride. The temperature of the mixture is maintained at a temperature of from 25°-30°C for 1 hour, yielding a solution of di-(6-methoxy-2-naphthyl)zinc.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][O:25][CH3:26])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:29][C:30]1([CH3:41])[CH2:35][C:34](B(O)O)=[CH:33][C:32]([CH3:40])([CH3:39])[NH:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]([N:8]1[C:6]2[N:7]=[C:2]([C:34]3[CH2:33][C:32]([CH3:40])([CH3:39])[NH:31][C:30]([CH3:41])([CH3:29])[CH:35]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][O:25][CH3:26])=[O:15])[C:5]=2[CH:10]=[N:9]1)([CH3:13])[CH3:12]
Reactant: CC1(C)C=C(B(O)O)CC(C)(C)N1
Reactant: COCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)nc2c1cnn2C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C2=CC(C)(C)NC(C)(C)C2)nc2c1cnn2C(C)C
Temperature: 100 °C
Yield: 44 %

Procedure:
To a stirred solution of 6-bromo-1-isopropyl-N-((4-(methoxymethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.06 g, 0.133 mmol) and (2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (0.043 g, 0.160 mmol) in dioxane/water mixture (1.5 mL+0.5 mL), Na2CO3 (0.5 g, 0.5 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.008 g, 0.007 mmol) was added and argon was purged again for 10 min Reaction mass was heated at 100° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to obtain crude material which was purified by column chromatography over silica gel to afford the desired product (44% yield). LCMS: 507.25 (M+1)+; HPLC: 99.64% (@ 254 nm) (Rt;5.159); 1H NMR (DMSO-d6, 400 MHz) δ 11.68 (bs, 1H), 8.91 (t, 1H), 8.26 (s, 1H), 7.77 (s, 1H), 6.80 (s, 1H), 6.09 (s, 1H), 5.24-5.18 (m, 1H), 4.51 (s, 2H), 4.35 (d, 2H, J=4.4 Hz), 3.32 (3H merged in DMSO peak), 2.43 (s, 2H), 2.17 (s, 3H), 1.49 (d, 6H, J=6 Hz), 1.24 (s, 6H), 1.14 (s, 6H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:8])[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: NC(=O)c1cnccc1N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccccc1C(=O)Nc1ccncc1C(N)=O

Procedure:
In a similar manner to Example 1 a) reaction of 2-propoxybenzoyl chloride (0.79 g), 4-aminonicotinamide (0.55 g) and triethylamine (0.40 g) in acetonitrile (12 ml) afforded a crude product which was recrystallised from ethanol-ether to afford 4-(2-propoxybenzamido)nicotinamide, 0.53 g, m.p. 164°-166° C.