Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].C1C[N:11]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OC([C:48]1[CH2:49][C:50]([C:66]([OH:68])=O)=[CH:51][C:52]2[CH:58]=[CH:57][C:56]([C:59]([F:65])([F:64])[C:60]([F:63])([F:62])[F:61])=[CH:55][C:53]=2[N:54]=1)=O)(C)(C)C.Cl.C(N)C>CN(C=O)C>[NH2:11][C:48]1[CH2:49][C:50]([C:66]([NH:3][CH2:1][CH3:2])=[O:68])=[CH:51][C:52]2[CH:58]=[CH:57][C:56]([C:59]([F:64])([F:65])[C:60]([F:61])([F:62])[F:63])=[CH:55][C:53]=2[N:54]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)C1=Nc2cc(C(F)(F)C(F)(F)F)ccc2C=C(C(=O)O)C1
Agent: CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(N)C1
Reaction time: 14 h
Yield: 7.5 %

Procedure:
To a solution of triethylamine (76 mg, 0.750 mmol), PyBOP (143 mg, 0.275 mmol) and (1E,4E)-2-(tert-butoxycarbonyl)-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylic acid (105 mg, 0.250 mmol) in DMF (4 mL) was added ethylamine hydrochloride (41 mg, 0.500 mmol). After stirring for 14 hours the mixture was partitioned between EtOAc (50 mL) and brine (100 mL). The phases were separated and the organic layer was washed with water (3×100 mL). The combined organics were dried and concentrated. The crude residue was taken up in CH2Cl2/TFA (˜1:1, 50 mL) and stirred at room temperature for 2 hours. The volatiles were removed under vacuum and the residue was partitioned between EtOAc and 10% Na2CO3 (1:1, 100 mL). The phases were separated and the aqueous was extracted with EtOAc (2×50 mL). The combined organics were dried and concentrated. The concentrate was purified via preparative TLC (2, 0.5 mm plates eluting with 10% MeOH/CH2Cl2 with 4-6 drops of NH4OH) to provide (1E,4E)-2-amino-N-ethyl-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide (6.5 mg, 8%). 1H NMR (CDCl3) δ 1.26 (t, 2H), 2.94 (s, 2H), 3.41-3.48 (m, 2H), 5.15 (br s, 1H), 6.08 (br s, 1H), 7.16 (s, 1H), 7.22 (d, 1H), 7.42 (d, 1H), 7.47 (s, 1H).
Reaction SMILES: [Mg].[CH:2]([CH:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=C.[C:12](=[O:14])=[O:13].Cl.[CH2:16](OCC)C>>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([CH2:16][C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1)=[CH2:2]
Reactant: O=C=O
Reactant: CCOCC
Reactant: C=CC(Cl)c1ccccc1
Agent: Cl
Agent: [Mg]
Product: C=Cc1ccc(CC(=O)O)cc1
Temperature: 5 °C
Yield: 22 %

Procedure:
5.3 g (220 mmol) of magnesium turnings are mixed with 150 ml of diethyl ether under an inert nitrogen atmosphere in a 250 ml three-neck round-bottom flask. 30.5 g (200 mmol) of vinylbenzyl chloride are then added, and the mixture is refluxed for 1 hour. CO2 is then passed into the suspension, cooled to 5° C., until no exothermicity can be detected with the aid of a thermometer (about 9 g). The mixture is then poured into 400 ml of 1N hydrochloric acid and extracted twice with ether. The combined ether phases are then washed with 500 ml of water, dried over magnesium sulfate and evaporated. The resultant oil is recrystallized from a mixture of 50 ml of toluene and 150 ml of n-hexane, giving 7.1 g (22% of theory) of 4-vinylphenylacetic acid as a white powder of melting point 94° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][N:33]1[C:37]([CH2:38][O:39][CH3:40])=[CH:36][N:35]=[CH:34]1)=[O:6])[CH:2]=[CH2:3].[CH3:41][I:42]>CC(C)=O>[I-:42].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][N+:33]1[C:37]([CH2:38][O:39][CH3:40])=[CH:36][N:35]([CH3:41])[CH:34]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CCn3cncc3COC)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CC(C)=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC[n+]3cn(C)cc3COC)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Reaction time: 3.5 h

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(5-methoxymethylimidazol-1-yl)ethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.79 g) in acetone (9.0 ml) was added methyl iodide (1.9 ml) at room temperature and the solution was allowed to stand for 3.5 hours. The solvent was evaporated to give allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(5-methoxymethyl-3-methyl-1-imidazolio)ethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate iodide (2.24 g) as a yellow solid. This compound was immediately used as the starting compound for the next step.
Reaction SMILES: [H][H].[N+:3]([C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10](=O)[CH3:11])([O-])=O.[N+](C(OC1C=CC=CC=1)C(=O)C)([O-])=O>[Ni].CO>[CH3:11][CH:10]1[NH:3][C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[O:8][CH2:9]1
Reactant: CC(=O)COc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Agent: CC(=O)C(Oc1ccccc1)[N+](=O)[O-]
Solvent: CO
Product: CC1COc2ccccc2N1
Temperature: 40 °C

Procedure:
Reaction conditions: 220 bar of hydrogen, reaction temperature 60° C. with a residence time of about 60-90 minutes. The space velocity was about 2 g of o-nitrophenoxyacetone per g of catalyst used and hour. The catalyst used was a nickel sponge metal catalyst from H. C. Starck, Amperkat Ni—Mo 3706 (exchange of the water under which the catalyst is stored for methanol). The yields in this step were 95+%; at least 100 g of nitrophenoxyacetone were converted per gram of theoretically dry catalyst. Good mixing was ensured by stirring. In order to prevent precipitation of the reactant solution, it was heated to 40° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[CH3:20].[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24].C(=O)(O)[O-].[Na+]>C1COCC1>[F:13][C:14]1[C:19]([Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=[CH:16][C:15]=1[CH3:20]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1cnccc1F
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1cncc(C)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A THF (1 mL) solution of diisopropylamine (160 μL; WAKO) was cooled to −78° C. under a nitrogen atmosphere followed by the dropwise addition of normal butyllithium (2.6 M, 430 μL; KANTO). The resulting mixture was stirred as it was for 30 minutes followed by the dropwise addition of a THF (1 mL) solution of 4-fluoro-3-methylpyridine (111 mg) and the resulting mixture was further stirred for 1 hour. Then tri-n-butyltin chloride (330 μL; TCI) was added and the resulting mixture was slowly raised to room temperature and then stirred for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture solution, to the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried and the solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=2)[CH2:4]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>C1COCC1>[CH3:1][N:2]([CH3:24])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:38]([NH:37][CH2:35][CH3:36])=[O:39])[N:16]=[C:12]3[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2cc(-c3cccnc3)cc3nc(N)nn23)C1
Reactant: CCN=C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(N3CCC(N(C)C)C3)n2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 5-(3-dimethylamino-pyrrolidin-1-yl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.190 g, 0.6 mmol), and NaHMDS (1.4 ml of 1 M solution in THF, 1.4 mmol) in anhydrous THF (100 ml) was stirred at room temperature for 45 minutes. EtNCO (0.5 ml, 6.3 mmol) was added and the resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with HCl (0.35 ml of 4 M solution in dioxane). Solvent was evaporated and the resultant material was purified by column chromatography on silica gel (1% NEt3, 0-10% MeOH in CH2Cl2 as eluant), followed by trituration in EtOH, to afford the desired compound as a solid. Mp. 248-250° C. MS (APCI+) 395 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:11][C:12]1[CH:27]=[CH:26][C:15]2[NH:16][C:17]([C:19]([O:21]C(C)(C)C)=[O:20])=[N:18][C:14]=2[CH:13]=1)(=[O:10])[CH3:9]>ClCCl>[C:8]([NH:11][C:12]1[CH:27]=[CH:26][C:15]2[NH:16][C:17]([C:19]([OH:21])=[O:20])=[N:18][C:14]=2[CH:13]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1ccc2[nH]c(C(=O)OC(C)(C)C)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc2[nH]c(C(=O)O)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.5 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a suspension of 1,1-dimethylethyl 5-(acetylamino)-1H-benzimidazole-2-carboxylate (0.155 g, 0.563 mmol) in dichloromethane (2 mL). After stirring at RT overnight, the solvent was evaporated to give the title compound (0.166 g, 88%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 10.17 (s, 1H), 8.19 (d, 1H), 7.61 (d, 1H), 7.40 (dd, 1H), 2.1 (s, 3 H). MS: m/z 218 (M−1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1.C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:26]([CH:23]4[CH2:25][CH2:24]4)=[O:27])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)C4CC4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 62.6 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.00 g, 3.10 mmol) and cyclopropanecarbonyl chloride (0.32 g, 3.10 mmol) in THF (35 mL), was added triethylamine (0.88 mL, 6.20 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 6 h then cooled to rt. The mixture was filtered and the filtrate diluted with EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (100 mL), water (2×75 mL), dried (MgSO4) and concentrated in vacuo to give cyclopropanecarboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.69 g, 63% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 2.96 min (98.96%); mp: 163-165° C.; 1H NMR (DMSO-d6) δ 0.62-0.78 (m, 4H), 1.63 (m, 1H), 1.95-2.17 (m, 1H), 2.53-2.67 (m, 2H), 2.79-3.00 (m, 1H), 4.46 (d, J=6.0 Hz, 2H), 5.15 (dd, J=5.4, 12.9 Hz, 1H), 7.67-7.79 (m, 2H), 7.89 (d, J=7.6 Hz, 1H), 8.77 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 6.44, 13.57, 21.99, 30.93, 42.05, 48.99, 121.83, 123.54, 129.74, 131.60, 133.35, 147.77, 166.99, 167.13, 169.82, 172.73, 172.94; Anal Calcd for C18H17N3O5+0.2H2O: C, 60.23; H, 4.89; N, 11.71. Found: C, 60.16; H, 4.54; N, 11.70.
Reaction SMILES: [C:1]1([CH:7]([N:11]2[C:16](=[S:17])[C:15]3[CH:18]=[N:19][NH:20][C:14]=3[N:13]=[CH:12]2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CN1CCOCC1.CCOC(C)=O>CN(C=O)C>[C:1]1([CH:7]([N:11]2[C:16](=[S:17])[C:15]3[CH:18]=[N:19][NH:20][C:14]=3[N:13]=[CH:12]2)[C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28][CH2:29]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)C(c1ccccc1)n1cnc2[nH]ncc2c1=S
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(C(c1ccccc1)n1cnc2[nH]ncc2c1=S)N1CCN(c2ccccn2)CC1
Reaction time: 8 h
Yield: 22 %

Procedure:
1-[3-(dimethylamino)propyl]-3-ethycabodiimide HCl (1.5 eq. mmol) and following 1-hydrobenzatriazole hydrate (HOBT) (0.5 eq. mmol) was added to a solution of 2-phenyl-(4-thioxo-1,4-dihydro-pyrazolo[3,4-d]pyrimidin-5-yl) acetic acid (XIVa) (1.0 eq. mmol) and a corresponding amine such as 1-(2-pyridyl)piperazine(1.5 eq. mmol) with 4-methylmorpholine (3.0 eq. mmol) in DMF at 0° C. The resulting mixture was stirred overnight at 0° C. to room temperature. The yellow reaction mixture was filtered off and washed well with EtOAc. The filtrate was extracted with brine, saturated NaHCO3, brine. The organic layer was dried over anhydrous Na2SO4, and then was concentrated under vacuum. The crude product was chromatographed using silica gel and eluted with CH2Cl2:EtOAc/1:1 to afford (XVIi) (0.029 g, 0.07 mmol, 22% yield) as a white solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2N=N1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.O>C1C=CC=CC=1>[C:15]1([C:8]2([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CCNC1
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(C2(N3CCCC3)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13 %

Procedure:
A mixture of 1,4-dioxaspiro[4.5]decan-8-one (10 g, 64 mmol), benzotriazole (7.62 g, 64 mmol) and pyrrolidine (5.26 ml, 64 mmol) in dry benzene (300 ml) was refluxed under an argon atmosphere in a water separator for 18 h. The reaction mixture was cooled to 25° C. and concentrated to small volume under vacuum and dried (aerated with argon). The crude product was taken up in dry tetrahydrofuran (50 ml) and cooled to 0° C. Phenyl magnesium bromide solution (650 ml, 1 mol/l in tetrahydrofuran) was added dropwise under protective gas. The cooling bath was removed and the mixture stirred for 18 h at 25° C. The reaction mixture was cooled to 0° C. again, hydrolysed with saturated ammonium chloride solution and extracted with ethyl acetate (3×300 ml). The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to small volume under vacuum. The crude product was purified by column chromatography (silica gel) with 5% methanol in dichloromethane. Yield: 13%
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])[CH:5]=[CH:4][CH:3]=1.[CH3:25]OC1C=C(C2OC3C=CC=CC=3N=2)C=CC=1B1OC(C)(C)C(C)(C)O1.BrC1C=C(C)C=CN=1>>[CH3:24][O:23][C:9]1[CH:10]=[C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[C:4]([CH3:25])[CH:3]=[CH:2][N:7]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Agent: Cc1ccnc(Br)c1
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1cc(C)ccn1

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (150 mg, 0.43 mmol) was reacted with 2-bromo-4-methylpyridine (47 μL, 0.43 mmol) to afford the desired 2-[3-methoxy-4-(4-methylpyridin-2-yl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.57 (s, 1H), 7.97–7.96 (m, 2H), 7.89 (s, 1H), 7.82–7.79 (m, 2H), 7.63–7.54 (m, 2H), 7.39–7.36 (m, 2H), 4.01 (s, 3H), 2.39 (s, 3H). MS (ESI) 317 (M+H)+.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[N:9]1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=1>O>[CH3:25][S:24][C:20]1[N:21]=[C:22]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[N:9]2)[CH:23]=[CH:18][N:19]=1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nccc(-n2nnc3ccccc32)n1
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
A 1 L round bottom flask was loaded with sodium hydride dispersion (10.0 g, 250 mmol, 60% in mineral oil) and 200 mL of DMF, and the resulting slurry cooled with an ice bath. Benzotriazole (18.02 g, 151 mmol) was added portionwise over a 10-12 min period. The reaction mixture was stirred for 10 min to allow gas evolution to subside; the ice bath was then removed and 4-chloro-2-methylthiopyrimidine (24.07 g, 150 mmol) was added. The resulting mixture was stirred at RT for 15 minutes, then placed in a 90° C. oil bath for 1.5 hour. The heating bath was turned off and the reaction mixture was allowed to slowly cool with stirring overnight. The reaction mixture was then poured into 500 mL of water and stirred for 20 min, and then filtered. The collected solids were washed with 3 portions of water and 3 portions of a mixture of hexanes/EtOAc (10:1 to 5:1), then dried to give 1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-benzotriazole as an off-white solid (27.05 g, 74% yield), mp=180.5-181.7° C.; MS=244 (M+H)+.
Reaction SMILES: C([Li])(CC)C.[CH2:6]([N:8]([CH2:18][CH3:19])[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[CH3:7].CN([CH:23]=[O:24])C.Cl>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH2:18]([N:8]([CH2:6][CH3:7])[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[CH:23]=[O:24])[CH3:19]
Reactant: CN(C)C=O
Reactant: CCN(CC)C(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C)cc1C=O
Temperature: 78 °C
Reaction time: 0.17 h

Procedure:
Tetramethylethyleneamine (6.20 g, 5336 mmol, 8.05 mL) was dissolved in anhydrous THF (100 mL) under argon and cooled to minus 78° C. s-Butyl lithium (1.30M, 53.36 mmol, 41.04 mL) was added to the solution slowly via syringe. The solution was stirred for 10 min at minus 78° C., then N,N-diethyl-4-methyl-benzamide (9.28 g, 48.51 mmol), dissolved in 50 mL of anhydrous THF was added to the reaction mixture over 15 min. The reaction was stirred for 1 h at minus 78° C. , the DMF (7.09 g, 97.02 mol, 7.51 mL) was added to the solution rapidly. The reaction mixture was allowed to slowly warm to room temp and stir for 12 h. The reaction mixture was poured into 1N HCl and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (3:1 hexane/ethyl acetate) Yield 7.98 g. 1H NMR (CDCl3, 300 MHz): δ 1.08 (t, 3H), 1.32 (t, 3H), 2.46 (s, 3H), 3.13 (q, 2H), 3.42 (a, 2H), 7.28 (d, J=8, 1H), 7.45 (d, J=7, 1H), 7.77 (s, 1H), 10.01 (s, 1H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH3:37])[N:17]2[N:38]=[CH:39][N:40]=[C:16]2[N:15]1[CH:41]1[CH2:45][CH2:44][O:43][CH2:42]1>C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([CH:41]4[CH2:45][CH2:44][O:43][CH2:42]4)[C:16]4[N:17]([N:38]=[CH:39][N:40]=4)[C:18]=3[CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[NH:34]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCOC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 12.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.42 g), sodium hydrogen carbonate (0.67 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[5-oxo-7-propyl-4-(tetrahydrofuran-3-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.18 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.078 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.066 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.025 g, 13%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[N:7][CH:8]=1.Cl[C:23]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:32][S:29]([C:28]1[C:23]([N:17]2[CH2:18][CH2:19][C:11]3[C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:1])[F:21])=[CH:8][N:7]=4)=[N:15][CH:14]=[N:13][C:12]=3[CH2:16]2)=[N:24][CH:25]=[CH:26][CH:27]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)c1cccnc1Cl
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1cccnc1N1CCc2c(ncnc2Nc2ccc(C(F)(F)F)cn2)C1
Temperature: 150 °C
Yield: 43.1 %

Procedure:
N-(5-(Trifluoromethyl)pyridine-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in a mixture of acetonitrile (2 mL). To the mixture was added 2-chloro-3-methanesulphonylpyridine (122 mg, 0.68 mmol) and N,N-diisopropylethylamine (0.23 mL, 0.68 mmol). The mixture was heated in a sealed tube at 150° C. in microwave (Model, Personal Chemistry) for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified by flash chromatography over silica gel using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (66 mg).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:12])[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[O:13]([CH2:20][CH:21]([OH:30])[CH2:22][NH:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][NH2:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1.O>C(Cl)Cl>[O:13]([CH2:20][CH:21]([OH:30])[CH2:22][NH:23][CH2:24][C:25]([CH3:28])([CH3:29])[CH2:26][NH:27][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1c(Cl)n(C)c(=O)n(C)c1=O
Reactant: CC(C)(CN)CNCC(O)COc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1c(NCC(C)(C)CNCC(O)COc2ccccc2)n(C)c(=O)n(C)c1=O

Procedure:
4.5 g. 4-Chloro-1,3,5-trimethylpyrimidine-2,6(1H,3H)-dione and 6.1 g. 1-phenoxy-3-(3-amino-2,2-dimethylpropylamino)-propan-2-ol (b.p. 159°-161° C./0.01 mm.Hg; obtained from phenyl glycidyl ether and 2,2-dimethyl-1,3-diaminopropane) are stirred for 50 hours at 80° C. in 8 ml. pyridine. The reaction mixture is taken up in methylene chloride, shaken with water, dried, evaporated and the residue obtained chromatographed on silica gel in the manner described in Example 29 to give 2.3 g. (24% of theory) of the desired product in the form of colorless crystals; m.p. 111°-112° C., after recrystallization from ethyl acetate.