Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][C:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[C:18]([C:31]([F:34])([F:33])[F:32])[N:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH3:15][C:16]1[CH:21]=[C:20]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[C:18]([C:31]([F:33])([F:32])[F:34])[N:17]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2nnc(N)nc2-c2ccccc2)cc(C(F)(F)F)n1
Yield: 90 %

Procedure:
6-bromo-5-phenyl-1,2,4-triazin-3-amine (1 molar eq.), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (1 molar eq.) and K2CO3 (1.5 molar eq.) are suspended in a mixture of 1,4-dioxane and water (2:1; 10 mL of solvent per gram of bromotriazine). The resulting mixture is degassed, treated with dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (2 mol %) and refluxed until full consumption of bromotriazine is observed by LCMS. The cooled reaction mixture is then diluted with water, extracted with DCM and passed through a phase separator. The organic phase is concentrated under reduced pressure and purified by gradient flash chromatography, eluting with mixtures of ethyl acetate and hexanes to afford 6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (90%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)(Cl)Cl>[C:17]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:9])[CH2:7][OH:8])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CO)NC(C)=O

Procedure:
To a suspension of about 46.57 g of L-serine methyl ester hydrochloride in about 3 liters of chloroform was added about 84 ml of triethylamine. This mixture was stirred until solution was complete, then about 21 ml of acetyl chloride was added dropwise. The mixture was then stirred under argon for about 2 days and the chloroform removed under reduced pressure. The residue was suspended in ethanol, filtered through a sintered glass funnel and the ethanol removed, giving about 49 g of the desired title compound [α]D26 =+36°±1° (CHCl3, 1.039%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH3:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC[O-].[Na+]>CCO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:19][C:17](=[O:18])[CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)C(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(C=Cc1ccc(F)cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 4-fluorobenzaldehyde (3.54 gm, 8.5 mmol) and 1,1-diphenylacetone (5.000 gm, 23.8 mmol) in absolute EtOH (50 ml) was treated with a solution of EtONa in EtOH (21% solution, 900 μl, 2.4 mmol). After stirring at room temperature for 22 hours, the mixture was concentrated to 35 ml and the solution was treated with HOAc (200 mg). The solution was cooled to 0° C. and the precipitate that had formed was collected by filtration and washed with cold EtOH. The title compound was obtained as a pale yellow solid (5.787 gm, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:26]4[NH:20][C:21](=[O:22])[NH:23][C:24]4=[O:25])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3ccc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 80 °C

Procedure:
To 5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.184 mmol) in 1 ml EtOH was added hydantoin (54 mg, 0.552 mmol) and piperidine (54 μL, 0.552 mmol). The mixture was heated in Microwave (200 W) for 60 minutes at 80° C. The solid formed was isolated by filtration and air dried to give 5-((5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=355)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH:19]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:27]3[CH2:28][CH2:29][N:24]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:25][CH2:26]3)[S:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: C1CCC(N2CCNCC2)C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Brc1ccc2nc(N3CCN(C4CCCC4)CC3)sc2c1
Yield: 97 %

Procedure:
To a solution of 6-bromo-2-chlorobenzothiazole (3 g, 12.1 mmol) in ethanol (50 mL) was added triethylamine (5.04 mL, 36.3 mmol) and 1-cyclopentylpiperazine (1.86 g, 12.1 mmol). The reaction mixture was heated at reflux for 16 h and then concentrated under reduced pressure. The residue was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford 4.3 g (99%) of 6-bromo-2-(4-cyclopentylpiperazin-1-yl)benzothiazole.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:46]=[S:47]1(=[O:71])[NH:60][C:59]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:53]2[C:48]1=[CH:49][CH:50]=[C:51]([CH2:61][CH2:62][O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH:52]=2.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17][N:60]3[C:59]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[C:53]4[C:48](=[CH:49][CH:50]=[C:51]([CH2:61][CH2:62][O:63][Si:64]([CH2:67][CH3:68])([CH2:69][CH3:70])[CH2:65][CH3:66])[CH:52]=4)[S:47]3(=[O:71])=[O:46])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: CC[Si](CC)(CC)OCCc1ccc2c(c1)-c1ccccc1NS2(=O)=O
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3c4ccccc4-c4cc(CCO[Si](CC)(CC)CC)ccc4S3(=O)=O)[C@H](C)[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate (365 mg, 1.0 mmol), triphenylphosphine (315 mg, 1.2 mmol), and 9,9-dioxo-6-(2-triethylsilanyloxy-ethyl)-10H-9-thia-10-aza-phenanthrene (429 mg, 1.1 mmol) in anhydrous tetrahydrofuran (7.3 mL) is cooled in an ice-bath and stirred under a nitrogen atmosphere while diisopropyl azodicarboxylate (0.24 mL, 1.2 mmol) is added dropwise over a few minutes. The resulting solution is stirred in the cold for 30 minutes, then diluted with chloroform, washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated under vacuum. The residue is purified by silica gel flash chromatography , eluting with hexane-ethyl acetate, to afford allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-[9,9-dioxo-6-(2-triethylsilanyloxy-ethyl)-10H-9-thia-10-aza-phenanthren-10-ylmethyl)-1-methyl-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=1[O:17]C)=[O:7].B(Br)(Br)Br>ClCCl>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=1[OH:17])=[O:7].[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]=1[OH:17])=[O:7]
Reactant: COC(=O)CCC(=O)c1c(C)cc(OC)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1c(C)cc(O)cc1O
Product: COC(=O)CCC(=O)c1c(C)cc(OC)cc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 34 %
Yield: 31 %

Procedure:
To a solution of 4-(2,4-dimethoxy-6-methyl-phenyl)-4-oxo-butyric acid methyl ester (1.0 g, 3.76 mmol) in dichloromethane (10 mL) was added 1 M BBr3 in dichloromethane (15.04 mL). The reaction mixture was stirred at room temperature for 48 hours then poured onto ice and extracted with EtOAc. The organic extracts were dried and concentrated in vacuo. The residue was dissolved in concentrated H2SO4 (0.2 mL) and MeOH (10 mL) and the mixture was heated at 75° C. for 1 hour. The mixture was concentrated in vacuo and the residue was purified by silica gel flash column chromatography to give 4-(2-hydroxy-4-methoxy-6-methyl-phenyl)-4-oxo-butyric acid methyl ester (0.300 g, 31%) and 4-(2,4-dihydroxy-6-methyl-phenyl)-4-oxo-butyric acid methyl ester (0.300 g, 34%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[CH:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[N:13][N:7]3[C:6]=2[CH:26]=1.F[C:28]1[CH:29]=CC2OC[C@@H]3[C@H](C4C=CC=CC=4)C(C(N(OC)C)=O)=NN3C=2[CH:52]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(Br)C=C>C1COCC1.C1(C)C=CC=CC=1>[CH2:29]([C:11]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:8]2[CH2:9][O:10][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:26][C:6]=3[N:7]2[N:13]=[C:12]1[C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])[CH:28]=[CH2:52]
Reactant: CON(C)C(=O)C1=NN2c3cc(F)ccc3OC[C@@H]2[C@@H]1c1ccccc1
Reactant: CON(C)C(=O)C1=NN2c3cc(F)ccc3OCC2C1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCC1(c2ccccc2)C(C(=O)N(C)OC)=NN2c3cc(F)ccc3OCC21
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
Either cis (1-7) or trans-8-Fluoro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (5-5, 4.8 g, 13.5 mmol) was dissolved in anhydrous THF (50 mL) and cooled to −78° C. in an acetone/dry ice bath under an N2 atmosphere. The resulting solution was treated with LHMDS (16.2 mL of a 1M toluene solution, 16.2 mmol) and stirred 2 minutes to produce a deep red color. Allyl bromide (2.3 mL, 26.9 mmol) was added neat and the solution was allowed to stir 10 minutes at −78° C. and then removed from the ice bath. Upon reaching ambient temperature, the reaction was judged complete by TLC and quenched by at addition of sat. aqueous NH4Cl (100 mL). The mixture was extracted with Et2O (3×100 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified using flash column chromatography (ISCO Redisep 120 g SiO2 column, 0-40% EtOAc/hexanes gradient) to provide pure 3-allyl-8-fluoro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (5-6; a racemic mixture): 1H NMR (300 MHz, CDCl3) δ 7.40-7.22 (m, 3H), 7.20-7.12 (m, 3H), 6.77 (dd, J=8.9, 5.2 Hz, 1H), 6.53 (dt, J=8.6, 3.1 Hz, 1H), 5.57 (m, 1H), 5.27 (d, J=16.8 Hz, 1H), 5.22 (d, J=7.6 Hz, 1H), 4.12 (dd, J=10.5, 3.5 Hz, 1H), 3.90 (s, 3H), 3.63 (dd, J=11.0, 3.6 Hz, 1H), 3.37 (dd, J=13.7, 6.0 Hz, 1H), 3.32 (s, 3H), 2.96 (m, 2H); MS (M+H+, C22H22FN3O3) 396.3 found 396.4 required.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:8][CH:9]([CH3:28])[C:10](=[C:13]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH:11]=O.[OH2:29]>>[CH3:8][CH:9]([CH3:28])[C:10](=[C:13]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)/[CH:11]=[CH:2]/[C:3]([O:4][CH2:5][CH3:1])=[O:29]
Reactant: CC(C)C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C1CCOC1
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C/C(=C(c1ccc(F)cc1)c1ccc(F)cc1)C(C)C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A THF (2.0 ml) solution of triethyl phosphonoacetate (EtO)2P(O)CH2COOEt (0.224 g, 0.198 ml, 1.00 mmol) was added at 0° C. under argon atmosphere to sodium hydride (content 60%, oil dispersion, 42 mg, 1.04 mmol) which had been washed with hexane, and the mixture was stirred for 30 minutes. To the mixture was added a THF (1 ml) solution of 3-methyl-2-bis(4-fluorophenyl)methylidenbutanal (0.286 g, 1.0 mmol) prepared according to the method described in Tetrahedron Lett., 29, 929 (1988). After stirring at room temperature overnight, the mixture was then diluted with water (25 ml) and extracted with hexane (30 ml×3 times). The organic layer was washed with water (30 ml×twice) and saturated sodium chloride aq solution and finally dried over anhydrous magnesium sulfate. Concentration in vacuo followed by purification by thin layer chromatography (silica gel, ethyl acetate:hexane=1:9) to give 0.28 g (79% yield) of ethyl (E)-5-methyl-4-bis(4-fluorophenyl)methylidene-2-hexenoate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([NH:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)(=[O:12])[CH3:11]>>[C:10]([NH:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[N:7]=[C:6]([NH:18][C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:10](=[O:12])[CH3:11])=[CH:20][CH:19]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:16][CH:15]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: CC(=O)Nc1ccc(Nc2ncc(F)c(Nc3ccc(NC(C)=O)cc3)n2)cc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-acetamidoaniline gave N2,N4-bis-(4-acetamidophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 14.82 min.; purity: 95%; MS (m/e): 395 (MH+); 1H NMR (DMSO-d6): δ 10.33 (1H, s), 10.14 (1H, s), 10.07 (2H, s), 8.39 (1H, d, J=5.1 Hz), 7.64 (8H, m), 2.15 (3H, s), 2.13 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([C@@H:17]1[O:19][CH2:18]1)[Cl:16]>>[Cl:16][CH2:15][C@H:17]([OH:19])[CH2:18][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: ClC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1nccn1C[C@@H](O)CCl

Procedure:
Alternatively, a mixture of 0.42 g (3.7 mmole) of 2-nitroimidazole, 85 mg (0.62 mmole) of anhydrous potassium carbonate, and 5 mL of (R)-(-)-epichlorohydrin is refluxed for 10 minutes then filtered while hot. The filtrate is concentrated and cooled to give a solid. Crystallization from ethanol and further processing as above gives 0.56 g of the product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:16]3[CH2:19][CH3:20])=[C:12]([NH2:26])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(C)C.Cl.[OH-].[OH-].[Pd+2]>[C:1]1([CH2:7][CH2:8][O:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([CH:21]4[CH2:25][CH2:24][CH2:23][O:22]4)[N:16]3[CH2:19][CH3:20])=[C:12]([NH2:26])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCn1c(-c2ccco2)nc2c(N)nc(OCCc3ccccc3)nc21
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(C)O
Product: CCn1c(C2CCCO2)nc2c(N)nc(OCCc3ccccc3)nc21
Yield: 46.7 %

Procedure:
To a solution of 2-(2-phenylethoxy)-8-(furan-2-yl)-9-ethyl-9H-purin-6-ylamine (150 mg, 0.43 mmol) in 45 mL of isopropanol and 2 drops of concentrated HCl was added 150 mg of Pd(OH)2, and the mixture was shaken with hydrogen at 170 psi and 65° C. for 7 hours. The catalyst was filtered off, washed with warm methanol, and the filtrate was concentrated to dryness. The residue was flash chromatographed on a silica gel column eluting with cyclohexane, -EtOAc-CH3OH (60:33:7) to give 2-(2-phenylethoxy)-8-(tetrahydrofuran-2-yl)-9-ethyl-9H-purin-6-ylamine (71 mg, 47%) as chromatographically pure solid: mp 121–123° C.; 1H NMR (Me2SO-d6) δ 1.33 (t, 3H, J=7.1 Hz, CH2CH3), 1.87–2.30 (m, 3H, H-3-Fur and H-4-Fur), 2.55–2.75 (m, 1H, H-3-Fur), 3.02 (t, 2H, J=6.9 Hz, CH2CH2Ph), 3.83 (m, 2H, H-5-Fur), 4.15 (q, 2H, J=7.1 Hz, CH2CH3), 4.41 (t, 2H, J=6.9 Hz, CH2CH2Ph), 5.14 (t, 1H, J=6.6 Hz, H-2-Fur), 7.17–7.40 (m, 7H, H-Ph and NH2). Anal. (C19H23N5O2) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:5]2=[N:6][C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)O.[H-].[Na+].[H][H].CI.CN(C)[CH:30]=[O:31]>O>[CH3:1][C:2]1[CH:3]=[C:4]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:5]2=[N:6][C:7]=1[CH2:8][C:10]1([O:31][CH3:30])[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH2:11]1
Reactant: [H][H]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(O)c2nc3c(cc2C)CCCCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC1(Cc2nc3c(cc2C)CCCCC3)C=CC(C)=CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(6,7,8,9-Tetrahydro-3-methyl-5H-cyclohepta[b]pyrid-2-yl)-1-(4-methylphenyl)methanol (2.0 g 0.007 m) was added to sodium hydride (0.35 g, 50% dispersion in oil, 0.007M, washed with 40-60 petrol) suspended in dimethylformamide(20 ml). After evolution of hydrogen had ceased, methyl iodide (0.5 ml) was added and the mixture stirred at room temperature for 0.5 hours. Water was added and the mixture extracted with diethyl ether. The combined ether extracts were treated with 2N hydrochloric acid. The aqueous acid solution was separated, basified with solid sodium carbonate and extracted with chloroform. The combined chloroform extracts were washed with water, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica and eluted with chloroform to give the title compound as a gum. This was dissolved in diethyl ether and treated with ethereal HCl to give the crystalline hydrochloride salt, 1.4 g m.p. 144°-6° C.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15])[CH2:2][C:3]#[CH:4].O1CCCC1.Br[C:22]1[N:23]=[CH:24][S:25][CH:26]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[S:25]1[CH:26]=[CH:22][N:23]=[C:24]1[C:4]#[C:3][CH2:2][CH2:1][N:5]1[C:9](=[O:10])[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:15]
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: Brc1cscn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1nccs1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
To 1184 mg of dichlorobis(triphenylphosphine)palladium, 322 mg of copper iodide, and 6.64 g of N-(3-butynyl)phthalimide were added 78 ml of tetrahydrofuran, 5.49 g of 4-bromothiazole, and 20.3 ml of triethylamine in a nitrogen atmosphere, and the mixture was stirred under reflux for 5 hours. After the stirring, the reaction mixture was cooled to room temperature and the solids were filtered. After concentrating the filtrate, the residue was purified by column chromatography (Wakogel C-200; toluene:ethyl acetate=4:1) to give 6.35 g of a phthalimide compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[OH:15][CH2:16][CH:17]([NH:24][C:25](=[O:29])[C:26](O)=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26](=[O:27])[C:25]([NH:24][CH:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][OH:15])=[O:29]
Reactant: O=C(O)C(=O)NC(CO)c1ccccc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C(=O)NC(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
The mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.256 g; 1.09 mmol), 2-(2-hydroxy-1-phenylethylamino)-2-oxoacetic acid (0.250 g; 1.19 mmol), HATU (0.413 g: 1.09 mmol) and N,N-diisopropylethylamine (0.474 mL; 2.71 mmol) in DMF (5 mL) was stirred at room temperature overnight and was concentrated under reduced pressure. The residue was dissolved in dichloromethane, the organic layer was washed with water and was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 1 to 10% methanol in dichloromethane) to yield 0.440 g of N1-(2-(5-chloro-1H-indol-3-yl)ethyl)-N2-(2-hydroxy-1-phenylethyl)oxalamide as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:30][CH2:31][Cl:32]>O>[Cl:32][CH2:31][CH2:30][O:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(O)ccc21
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCl)ccc21
Temperature: 70 °C

Procedure:
1-Ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.2 g) and potassium carbonate (0.95 g) were added to 50% hydrous acetonitrile (24 ml). The mixture was heated to 70° C. to be dissolved. 1-Bromo-2-chloroethane (1.9 ml) was added, and the mixture was heated under reflux for 7 hours. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried by sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound (1.4 g) as a colorless oily matter.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[C:23]([O:27][CH3:28])=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14]
Reactant: COc1cccc(F)c1B(O)O
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)cccc12
Product: COc1cccc(F)c1-c1cccc2c(N)c(C(=O)NC3CCC3)nnc12
Yield: 19.3 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclobutyl-cinnoline-3-carboxamide (145 mg) and 2-fluoro-6-methoxy-phenyl boronic acid (191 mg) were reacted to afford the title compound (32 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.20 (d, 1H), 8.44 (m, 1H), 7.76 (m, 2H), 7.44 (m, 1H), 6.99 (d, 1H), 6.90 (t, 1H), 4.49 (m, 1H), 3.65 (s, 3H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=367 (M+H).