Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:9]([F:13])=[CH:10][C:11]=1[Cl:12])[NH2:8])[CH:2]=[CH2:3].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([N:8]2[C:17](=[O:18])[C:16]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]3[C:14]2=[O:19])[C:9]([F:13])=[CH:10][C:11]=1[Cl:12])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCOc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl

Procedure:
A mixture of 20.2 g of 19A and 14.8 g of phthalic anhydride in 300 mL of toluene was treated with 1.01 g of triethylamine and heated to reflux for 16 hours with a Dean-stark trap to effect azeotropic removal of water. The toluene was removed in vacuo, the residue was dissolved in 800 mL of methylene chloride, and treated with 35 g charcoal. After filtration through celite and concentration of solvent in vacuo, the residue was recrystallized from ethanol to afford N-[3-(allyloxy)-4-chloro-6-fluorophenyl]phthalimide (41A) as tan crystals, m.p.: 148°-150° C.
Reaction SMILES: [C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:21]O>>[C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([O:3][CH3:21])=[O:2]
Reactant: CO
Reactant: O=C(O)C=Nc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)C=Nc1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Yield: 75 %

Procedure:
5 g (21.8 mmol) of N-carboxymethylene-4-chloro-anthranilic acid are introduced into 50 ml of methanol, and 222 mg (2.3 mmol) of sulfuric acid are added. The mixture is heated under reflux for 4 hours and then cooled to room temperature. The product which has precipitated out is filtered off with suction, washed with methanol and dried. 4.0 g (16.4 mmol; 75%) of N-carbomethoxymethylene-4-chloro-anthranilic acid are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:29]=[CH:30][CH:31]=[CH:32][C:4]=2[N:3]=1.[CH:33]([N:36]=[C:37]=[O:38])([CH3:35])[CH3:34]>C1COCC1>[CH:33]([NH:36][C:37]([N:20]1[CH2:19][CH2:18][C:17]([CH2:16][CH2:15][N:14]2[CH:12]3[CH2:11][CH2:10][CH:9]2[CH2:8][CH:7]([N:6]2[C:5]4[CH:29]=[CH:30][CH:31]=[CH:32][C:4]=4[N:3]=[C:2]2[CH3:1])[CH2:13]3)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21]1)=[O:38])([CH3:35])[CH3:34]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)NC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole (20 mg, 0.047 mmol) in THF (2 mL) was added isopropyl isocyanate (4.3 mg, 0.047 mmol). The resulting mixture was stirred at ambient temperature overnight. After evaporation of the solvent, the residue was purified on silical gel, eluting with a gradient of 10-30% methanol in ethyl acetate to afford N-isopropyl-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboxamide as white solid (15 mg, 63%). 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=7.2 Hz, 1H), 7.43-7.38 (m, 2H), 7.34-7.24 (m, 4H), 7.22-7.15 (m, 2H), 4.67 (br, 1H), 4.24 (d, J=7.3 Hz, 1H), 3.99 (m, 1H), 3.62-3.58 (m, 2H), 3.30 (br, 2H), 3.23-3.16 (m, 2H), 2.62 (s, 3H), 2.42 (br, 2H), 2.25-2.20 (m, 2H), 1.98-1.83 (m, 9H), 1.68 (br, 2H), 1.17 (d, J=6.4 Hz, 6H). HRMS m/z (M+H)+ calcd: 514.3546, obsd: 514.3530.
Reaction SMILES: C([NH2:3])C.C([NH:6][C:7](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)SC)#N>>[N:16]1[CH:17]=[CH:18][N:19]=[CH:20][C:15]=1[CH2:14][S:13][CH2:12][CH2:11][NH:10][C:7]([NH2:6])=[NH:3]
Reactant: CSC(=NCCSCc1cnccn1)NC#N
Reactant: CCN
Product: N=C(N)NCCSCc1cnccn1

Procedure:
Anhydrous ethylamine is reacted with N-cyanoN'-[2-(2-pyrazinylmethylthio)ethyl]- S-methylisothiourea by the procedure of Example 4 to give N-cyano-N'-ethyl-N"[2-(2-pyrazinylmethylthio)ethyl]guanidine.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][CH:23]=[C:24]([CH:26]=O)[N:25]=2)=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[N:25]=2)=[CH:19][CH:20]=1
Reactant: O=Cc1csc(-c2ccc(F)cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2csc(-c3ccc(F)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
tert-Butyl piperazine-1-carboxylate (62 mg, 0.33 mmol) was added to a solution of 2-(4-fluorophenyl)thiazole-4-carbaldehyde (70 mg, 0.34 mmol) in 1,2-dichloroethane (3 mL) at 0° C., followed by sodium triacetoxyborohydride (85 mg, 0.4 mmol). The reaction mixture was allowed to warm up to room temperature, stirred for 16 h and further heated to 50° C. for another 4 h. The reaction mixture was quenched with 10% aqueous NaHCO3 and extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 35% EtOAc in petroleum ether) to afford tert-butyl 4-((2-(4-fluorophenyl)thiazol-4-yl)methyl)piperazine-1-carboxylate (82 mg, yield 64%). 1H NMR (300 MHz, CDCl3) δ 7.96-7.91 (dd, J=9.0 Hz, 5.3 Hz, 2H), 7.15-7.09 (m, 3H), 3.75 (s, 2H), 3.50-3.46 (m, 4H), 2.55-2.52 (m, 4H), 1.46 (s, 9H). MS (ESI) m/z: Calculated for C19H24FN3O2S: 377.16. found: 378.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24][OH:25])[O:15][C:14]3=[O:26])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].IC.[C:33]([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24][O:25][CH3:33])[O:15][C:14]3=[O:26])=[CH:11][CH:12]=2)=[CH:27][CH:28]=1
Reactant: O=C([O-])O
Reactant: O=C1O[C@@H](CO)[C@H](c2ccccc2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@@H]1OC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-phenyloxazolidin-2-one (14 mg, 0.035 mmol) in THF (1 mL) was added NaH (˜5 mg) and the reaction was stirred for 10 min. at room temperature. Iodomethane (˜0.01 mL) was added and the reaction was stirred for an additional 2 h. NaHCO3 aqueous solution was added to quench, followed by dilution with water and ethyl acetate. The organic phase was washed with brine, dried (MgSO4), and concentrated. Flash chromatography (0-30% ethyl acetate/hexanes) yielded 8 mg (57%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ (ppm) 7.23-7.32 (m, 7H), 7.16-7.19 (m, 2H), 6.78-6.82 (m, 4H), 5.16 (d, 1H, J=5.7 Hz), 4.36 (dd, 1H, J=9.3, 3.9 Hz), 3.63 (ddd, 2H, J=18.4, 11.0, 4.1), 3.41 (s, 3H). HPLC-MS calculated C23H20ClNO4 (M+H+): 410.1, found: 410.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]([NH:16]C(OC(C)(C)C)=O)([CH3:15])[C:10]2([CH2:12][CH2:11]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[OH-].[Al+3].[Li+].[OH-].[OH-].[OH-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O.ClCCl>[NH2:16][C:13]1([CH3:15])[C:10]2([CH2:12][CH2:11]2)[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1(C)CN(Cc2ccccc2)C(=O)C12CC2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC1(N)CN(Cc2ccccc2)CC12CC2
Reaction time: 0.67 h

Procedure:
To a dichloromethane solution (15 mL) of the (−)-5-benzyl-7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptan-4-one (950 mg, 2.88 mmol) was added trifluoroacetic acid (7.5 mL) at room temperature, and stirred at the same temperature for 40 minutes. The solvent was removed under reduced pressure, and the solution was subjected to azeotropy with toluene (twice). After that, to this solution was added a saturated aqueous solution (30 mL) of sodium bicarbonate, and the mixture was extracted with chloroform (100 mL and 50 mL×2). To the combined organic layer was added anhydrous sodium sulfate to dry the solution. The drying agent was removed by filtration, and then the solvent was removed under reduced pressure. Thus-obtained residue was dissolved in tetrahydrofuran (30 mL), to this solution was added lithium aluminum hydroxide (218 mg, 5.74 mmol) with stirring under cooling with ice, and the mixture was stirred at the same temperature for 1 hour. Furthermore, to this solution was added lithium aluminum hydroxide (109 mg, 2.87 mmol), and the mixture was stirred at room temperature for 2.5 hours. After that, this solution was cooled with ice and to this solution was cautiously added water (0.31 mL), 15% aqueous solution (0.31 mL) of sodium hydroxide and water (0.93 mL) sequentially. Thus-obtained mixture was stirred at room temperature overnight. And then to this mixture was added anhydrous sodium sulfate to dry the mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to obtain a crude product of 7-amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane as transparent and colorless oil. The obtained crude product was used for the subsequent reaction without further purification.
Reaction SMILES: [C:1]1([CH:7](O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(Cl)=NC(Cl)=NC=1[Cl:12]>>[Cl:12][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(O)c1ccccc1
Product: CC(Cl)c1ccccc1

Procedure:
Using a procedure analogous to that of Example 1, 100 g (0.82 mol) of 1-phenylethane-1-ol is reacted with 97.6 g (0.529 mol) of cyanuric chloride over a period of 14 hours at a reaction temperature of 90° C. After phase separation, treatment with sodium hydroxide and purification by distillation, 1-chloro-1-phenylethane having a purity of>99% and containing<0.3% of isomeric alkyl chlorides is obtained.
Reaction SMILES: [C:1](Cl)(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[CH2:9]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:10]=[CH2:11].[OH-].[Na+]>C(Cl)Cl>[CH2:9]([N:12]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:1](=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6])[CH:10]=[CH2:11]
Reactant: C=CCNCCc1ccccc1
Reactant: C/C=C/C=C/C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CCN(CCc1ccccc1)C(=O)/C=C/C=C/C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
Sorboyl chloride (3.53 g) was added to a mixture of 4.0 g of N-allylphenethylamine, 25 mL of methylene chloride and 25 mL of 15% aqueous sodium hydroxide, keeping the temperatue below 15°. The mixture was stirred in an ice bath for 1 hour, then at room temperature overnight. The aqueous layer was extracted several times with toluene and the combined organic phases were washed successively with 5% hydrochloric acid, water, and 10% sodium carbonate solution. Removal of the solvents gave 6.37 g of N-allyl-N-phenethylsorbamide. This product was heated under reflux in 50 mL of p-xylene for 10 hours. Removal of the solvent gave 6-methyl-3a,4,5,7a-tetrahydroisoindolin-1-one as a mixture of isomers still containing about 10% of the uncyclized starting material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:10])[C:8]=1[F:9])[NH2:5].[O:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.C(O)(=O)C1C=CC=CC=1.[Na].[BH4-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: O=C1CCOCC1
Reactant: Nc1cc(F)c(F)c(F)c1
Agent: O=C(O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: Fc1cc(NC2CCOCC2)cc(F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.4 %

Procedure:
To a mixture of 3,4,5-trifluoroaniline (3.70 g, 25.1 mmol), tetrahydro-4H-pyran-4-one (2.52 g, 25.1 mmol), and benzoic acid (3.07 g, 25.1 mmol), was added sodium NaBH4 (0.95 g, 25.1 mmol), the whole mixture was stirred at room temperature for 1.5 h. After quenching with the reaction mixture with 1 M aq. NaOH under cooling with ice, the whole mixture was extracted with Et2O. The extract was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography of the residue (hexane:EtOAc=3:2) gave 4-(3,4,5-trifluorophenyl)aminotetrahydropyran (2.40 g, 41%) as a white powder.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[O:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][NH:14][CH2:13][CH2:12]1>C(OCC)(=O)C>[CH:1]([N:14]1[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:11][CH2:12][CH2:13]1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CNCCO2
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=CN1CCOc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (30 ml),was added dropwise to formic acid (90 ml) at room temperature and after the mixture was stirred for 30 minutes, a solution of 2,3,4,5-tetrahydro-1,4-benzoxazepine (13.0 g) in ethyl acetate (50 ml) was added dropwise at:room temperature. The mixture was then stirred for 30 minutes, after which it was diluted with ice-water and extracted with ethyl acetate. The extract was washed successively with water, aqueous solution of sodium hydroxide (NaOH/H2O), and saturated aqueous solution of sodium chloride (NaCl/H2O) and dried over anhydrous magnesium sulfate (MgSO4). The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to provide the title compound (14.4 g) as a viscous oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[C:5]2[CH2:10][N:9]([CH:11]([CH3:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1.[F:21][C:22]1[CH:23]=[C:24]([NH:37][C:38]([NH:40][CH2:41][CH2:42][OH:43])=[O:39])[CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].COC1CCCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.O>[F:21][C:22]1[CH:23]=[C:24]([NH:37][C:38]([NH:40][CH2:41][CH2:42][OH:43])=[O:39])[CH:25]=[CH:26][C:27]=1[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[C:5]2[CH2:10][N:9]([CH:11]([CH3:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COC1CCCC1
Product: CC(C)N1Cc2nc(-c3ccc(NC(=O)NCCO)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 4.8 %

Procedure:
A solution of (S)-4-(2-chloro-6-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 22) (109 mg, 0.367 mmol), 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-hydroxyethyl)urea (intermediate 32) (151 mg, 0.466 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (15 mg, 0.018 mmol) and sodium carbonate (117 mg, 1.10 mmol) in 2 ml of a 7:3:1 mixture of CPME:H2O:EtOH respectively was heated in the microwave at 130° C. for 1 hour. The reaction was concentrated in vacuo and the residue redissolved in a mix of MeOH/DCM. It was loaded onto an SCX cartridge and washed with two column volumes of MeOH/DCM before being eluted with 2M NH3 in MeOH and concentrated in vacuo. The sample was then purified via preparative HPLC at high pH to yield the title compound (8 mg, 5%).
Reaction SMILES: [I:1][CH:2]1[CH:6]2[O:7][C:8](=[O:14])[CH:9]3[CH:10]([C:11]([OH:13])=O)[CH:3]1[CH2:4][CH:5]23.Cl.[NH2:16][CH2:17][C:18]#[N:19].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.C(N(CC)CC)C>CN(C)C=O>[C:17]([CH2:18][NH:19][C:11]([CH:10]1[CH:3]2[CH2:4][CH:5]3[CH:6]([CH:2]2[I:1])[O:7][C:8](=[O:14])[CH:9]13)=[O:13])#[N:16]
Reactant: N#CCN
Reactant: O=C(O)C1C2CC3C(OC(=O)C31)C2I
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCNC(=O)C1C2CC3C(OC(=O)C31)C2I
Temperature: 0 °C
Reaction time: 4.5 h

Procedure:
To (3R/S,3aR/S,5S/R,6S/R,6aS/R,7S/R)-6-iodo-2-oxohexahydro-2H-3,5-methano-cyclopenta[b]furan-7-carboxylic acid (1.51 g, 4.90 mmol) was added aminoacetonitrile hydrochloride (502 mg, 5.43 mmol) and) benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (2.56 g, 4.91 mmol. After adding dimethylformamide (10 mL), the reaction mixture was cooled to 0° C. and triethylamine (1.7 mL, 12 mmol) was added. After stirring the reaction mixture at ambient temperature for 4.5 h, the product was extracted into ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. Chromatography of the residue on silica gel with 1:1 ethyl acetate:hexanes eluent gave (3R/S,3aR/S,5S/R,6S/R,6aS/R,7S/R)-N-(cyanomethyl)-6-iodo-2-oxohexahydro-2H-3,5-methanocyclopenta[b]furan-7-carboxamide as a colorless syrup.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][CH:9]2[O:14]CCO[CH2:10]2)[CH2:5][CH2:4][N:3]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CC1C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>CCOC(C)=O>[O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][C:9](=[O:14])[CH3:10])[CH2:5][CH2:4][N:3]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CN1CCC(CCC2COCCO2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)CN1CCC(CCC(C)=O)C1=O

Procedure:
A solution of 2-4 (1.1 g, 3.9 mmol), p-TSA (5 mg) and acetone (50 mL) was heated at reflux for 1 hr. The cooled reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentration to afford 2-5 as a yellow oil.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([I:26])[N:21]=4)[S:16][C:17]=3[CH3:18])[CH:10]=[N:9]2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O>[I:26][C:22]1[N:21]=[C:20]([NH:19][C:15]2[S:16][C:17]([CH3:18])=[C:13]([C:11]3[CH:12]=[N:8][NH:9][CH:10]=3)[N:14]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4cccc(I)n4)sc3C)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1sc(Nc2cccc(I)n2)nc1-c1cn[nH]c1
Yield: 33.7 %

Procedure:
According to Scheme 2 Step 5: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-methylthiazol-2-yl)-6-iodopyridin-2-amine (0.27 mmol, 136 mg) in TFA (1.4 mL) was microwaved for 5 minutes at 140° C. The reaction mixture was neutralized with a saturated solution of Na2CO3 and the aqueous phase was extracted with DCM. The organic phase was dried over MgSO4, was filtered and was concentrated. The resulting crude product was purified by flash chromatography over silica gel using DCM/MeOH (100:0 to 90:10) as eluent to yield N-(6-iodopyridin-2-yl)-5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-amine (91 μmol, 34 mg, 34%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6](Br)=[CH:5][N:4]=1)#[N:2].[OH-].[Na+].Cl.N[C:17](N)=O>[Ni].O.C(O)C>[N:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[CH:1]=[N:2][CH:17]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: NC(N)=O
Agent: [Ni]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1cnc2cncnc2c1

Procedure:
In another embodiment, Scheme 7B provides the preparation of 2,4,7-trisubstituted pyrido-pyrimidine compounds which are encompassed by formula (I), where X is N, Y and Z are CH, and R1, R3, and R6 are H. Specifically, 2-cyano-3-nitro-5-bromopyridine [CC1] is converted to the corresponding amide [DD1] using Raney Nickel and H2. Desirably, the reaction is performed in the presence of ethanol for about 14-20 h. Amide [DD1] is then converted to the corresponding acid [EE1] using NaOH (5 eq) and H2O at about 110° C. for about 5 h, followed by work-up using dil. HCl. Acid [EE1] is cyclized using urea (10 eq) at about 200° C. for about 3 h to form pyrido-pyrimidine intermediate [FF1]. Intermediate [FF1] is reacted with POCl3 and DIPEA at about 130° C. for about 10 h. The 4-position of the pyrido-pyrimidine is then substituted using morpholine in CH2Cl2 at a temperature of about 0° C. for about 30 min to form compound [HH1]. Compound [HH1] is then coupled with R2 using R2B(OR)2, PdCl2(PPh3)2 (0.05 eq), Na2CO3 (1.5 eq), DMF, and H2O at about 90° C. for about 2-3 h to form compound [JJ1]. The title compound is then formed by reacting compound [JJ1] with PdCl2(PPh3)2 (0.05 eq), Cs2CO3 (2 eq), DMF, and H2O at a temperature of about 90° C. for about 2-3 h. Alternatively, the title compound may be formed by reacting intermediate [JJ1] with PdCl2(PPh3)2 (0.05 eq) and Cs2CO3 (2 eq) in toluene, ethanol, and H2O at a temperature of about 90° C. for about 2-3 h.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=4)[S:16][C:17]=3[F:18])[CH:10]=[N:9]2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O>[F:18][C:17]1[S:16][C:15]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)=[N:14][C:13]=1[C:11]1[CH:12]=[N:8][NH:9][CH:10]=1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4ccc(F)cn4)sc3F)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(Nc2nc(-c3cn[nH]c3)c(F)s2)nc1
Yield: 11.4 %

Procedure:
According to Scheme 7 Step 2: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-fluorothiazol-2-yl)-5-fluoropyridin-2-amine (1.85 mmol, 739 mg) in TFA (2 mL) was microwaved for 8 minutes at 120° C. The reaction mixture was neutralized with a saturated solution of Na2CO3 (100 mL). The aqueous phase was filtered to afford a brown solid. The resulting crude product was purified by flash chromatography over silica gel using DCM as eluent to yield 5-fluoro-N-(5-fluoropyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine (0.21 mmol, 60 mg, 95%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1.[CH2:25](I)[CH3:26]>>[NH2:1][C:2]1[N:3]=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH2:25][CH3:26])[CH:18]=2)=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CCI
Reactant: Nc1nc(-c2ccco2)c(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Product: CCn1cc(-c2c(-c3ccco3)nc(N)nc2-c2ccco2)ccc1=O

Procedure:
The title compound was synthesized in a similar manner to Example 66 using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and ethyl iodide.
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH2:9]([N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:12][CH2:13][CH2:14][NH2:15])[CH3:10]>CO>[CH2:9]([N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:12][CH2:13][CH2:14][NH:15][C:6]1[C:1](=[O:8])[CH:2]=[C:3]([NH:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:9][CH3:10])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[C:4](=[O:7])[CH:5]=1)[CH3:10]
Reactant: CCN(CCCN)Cc1ccccc1OC
Reactant: O=C1C=CC(=O)C=C1
Solvent: CO
Product: CCN(CCCNC1=CC(=O)C(NCCCN(CC)Cc2ccccc2OC)=CC1=O)Cc1ccccc1OC
Reaction time: 6 h
Yield: 45.6 %

Procedure:
To a solution of p-benzoquinone (0.1 g; 0.92 mmol) in 70 ml of MeOH was added when cold N1-ethyl-N1-(2-methoxy-benzyl)-propan-1,3-diamine (0.45 g; 2.0 mmol). The reaction mixture was agitated at e.t. and out of the light for 6 h, the was evaporated in a vacuum to give a crude material which was purified by flash chromatography. Eluting with CH2Cl2/MeOH/NH4OH 9.75:0.25:0.025 obtained 0.23 g of the compound XII as a pure red solid on TLC (eluant: CHCl3/MeOH/NH4OH 9.5:0.5:0.05). Yield 45%; 1H NMR (free base; CDCl3) δ: 1.11 (t, 6H), 1.72-1.85 (m, 4H), 2.56 (q, 8H), 3.18 (q, 4H), 3.62 (s, 4H), 3.82 (s, 6H), 5.26 (s, 2H), 6.83-6.95 (m, 4H), 7.19-7.43 (m, 4H+2H exchangeable with D2O); EI-MS: m/z=548 (M+).