Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Mg]Cl)(C)C.CN([CH:19]=[O:20])C.Cl>C1COCC1>[F:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([CH:19]=[O:20])[CH:9]=1
Reactant: N#Cc1ccc(F)cc1Br
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(F)cc1C=O
Temperature: -30 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
To a solution of 2-bromo-4-fluorobenzonitrile (5.0 g, 25.0 mmol) in anhydrous THF (20 mL) is added iPrMgCl 2.01\4 in THF (15.0 mL, 30.0 mmol) at −30° C. The solution is stirred at −30° C. for 3 hours and DMF (5.80 mL, 75.0 mmol) is added. The reaction mixture is allowed to warm to room temperature and is stirred for 1 hour. The solution is cooled to −10° C., 2M hydrochloric acid (37 mL) is added and the solution is stirred for 20 minutes. The solution is concentrated in vacuo to −⅓ original volume and extracted into EtOAc (3×). The combined organics are then dried (Na2SO4), filtered and concentrated to afford 4-fluoro-2-formyl benzonitrile (3.9 g, 71%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:6][CH:5]=1.[CH3:15][C:16]1[CH:17]=[C:18]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:29]=[C:28]([C:36](O)=O)[N:27]=2)[CH:19]=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23]>>[CH3:15][C:16]1[CH:17]=[C:18]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[N:29]=[C:28]([C:36]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:6][CH:5]=4)[N:14]=3)[N:27]=2)[CH:19]=[CH:20][C:21]=1[C:22]([F:23])([F:24])[F:25]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(C(=O)O)n2)ccc1C(F)(F)F
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3nc(-c4ccc(S(N)(=O)=O)cc4)no3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (0.14 g, 0.65 mmol) and 4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.9) (0.175 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.147 g, 56%). MS (ISN) 528.3 [(M−H)−]; mp 261° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH:22]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1.C(N(CC)CC)C>CN1CCCC1=O>[NH2:22][CH2:21][CH:18]1[CH2:19][CH2:20][N:15]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[N:13][CH:12]=[CH:11][N:10]=3)[CH:3]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: Clc1cc(Nc2cnccn2)ncn1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: NCC1CCN(c2cc(Nc3cnccn3)ncn2)CC1
Temperature: 140 °C
Yield: 16.1 %

Procedure:
A mixture of 6-chloro-N-(pyrazin-2-yl)pyrimidin-4-amine (20 mg, 0.096 mmol), tert-butyl N-(4-piperidinylmethyl)carbamate (41 mg, 0.193 mmol) and triethylamine (27 μL, 0.193 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was heated at 140° C. for 10 minutes using microwave irradiation. The mixture was concentrated in vacuo and the residue purified using preparative HPLC. The purified solid was dissolved in dichloromethane (4 mL) and treated with trifluoroacetic acid (4 mL) for 1 hour at room temperature. The solution was applied to a MP-TsOH SPE cartridge, washed, then eluted with 2N ammonia and concentrated to give N-(6-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)pyrazin-2-amine (4.4 mg, 16%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[C:12]2[C:19]([CH3:20])=[CH:18][S:17][C:13]=2[N:14]=[CH:15][N:16]=1.[H-].[Na+].[CH3:23]I.O>CN(C)C=O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[N:10]([C:11]1[C:12]2[C:19]([CH3:20])=[CH:18][S:17][C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:23]
Reactant: CI
Reactant: Cc1csc2ncnc(NC3Cc4ccccc4C3)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc2ncnc(N(C)C3Cc4ccccc4C3)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A compound of the above Example 1, 4-(2-indanylamino)-5-methylthieno[2,3-d]pyrimidine (29 mg, 0.10 mmol), was dissolved in dry dimethylformamide (0.5 ml), to which sodium hydride (4.4 mg, 0.11 mmol) was added. After the mixture was stirred at room temperature for 10 minutes, methyl iodide (7.0 μl, 0.11 mmol) was added to the reaction mixture, which was further stirred at room temperature for 30 minutes. Water was added to the reaction mixture, which was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (20 mg, 0.070 mmol) having the following physical properties:
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:5][C:4]=1[CH3:19])=O.C1(P(=[CH:39][C:40]([O:42][CH3:43])=[O:41])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[C:16]([NH:15][C:12]1[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:6]2[S:7][C:3](/[CH:1]=[CH:39]/[C:40]([O:42][CH3:43])=[O:41])=[C:4]([CH3:19])[CH:5]=2)[N:11]=1)(=[O:18])[CH3:17]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1nc(CCc2cc(C)c(C=O)s2)cs1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/c1sc(CCc2csc(NC(C)=O)n2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
To a solution of N-{4-[2-(5-formyl-4-methylthiophen-2-yl)ethyl]-1,3-thiazol-2-yl}acetamide (468.0 mg, 1.590 mmol) in chloroform (4.7 ml) was added dropwise a solution of methyl (triphenyl phosphoranylidene)acetate (797.4 mg, 2.385 mmol) in chloroform (2 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Merck 9385 60 g, ethyl acetate:dichloromethane=1:8) to give methyl (2E)-3-(5-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}-3-methylthiophen-2-yl)-2-propenoate (591.6 mg, containing triphenylphosphineoxide) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[N:18]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CCO>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:26][CH2:25][CH2:24][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: NCCN1CCOCC1
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(NCCN2CCOCC2)c([N+](=O)[O-])c1

Procedure:
A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (1.00 g, 4.16 mmol), 2-(4-morpholinyl)ethanamine (0.600 mL, 4.58 mmol) in 80% aq. EtOH (50 mL) was refluxed for 4 hours. The reaction was then concentrated in vacuo, and the residue was taken up into EtOAc (40 mL). The organic phase was washed with saturated NaHCO3 (2×10 mL), and the combined aqueous phases were extracted with additional EtOAc (2×20 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound. The crude product was purified by silica gel column chromatography (100% EtOAc to 5% triethylamine/EtOAc) to provide the title compound (1.12 g, 77%) as a bright yellow solid. 1H-NMR (CDCl3): δ 8.67 (s, 1H), 8.28 (d, J=1.2 Hz, 1H), 7.56 (dd, J=8.8 Hz, J=1.6 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 3.77 (t, J=5.2 Hz, 4H), 3.55–3.20 (br m, 6H), 2.74 (t, J=6.4 Hz, 2H), 2.53 (br s, 4H), 1.22 (t, J=6.8 Hz, 6H). MS (ESI) (M+H)+=351.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([I:7])[CH:4]=[N:3]1.[N:8]1([C:14](Cl)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>>[I:7][C:5]1[CH:4]=[N:3][N:2]([O:1][C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:15])[CH:6]=1
Reactant: On1cc(I)cn1
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(On1cc(I)cn1)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxy-4-iodopyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (99%, crystals).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.[F:51][C:52]1[CH:57]=[CH:56][C:55]([C@H:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=1>C1COCC1>[F:51][C:52]1[CH:57]=[CH:56][C:55]([C@H:58]([NH:60][C:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]2)=[O:17])[CH3:59])=[CH:54][CH:53]=1
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trans-4-(tert-Butoxycabonylamino)cyclohexanecarboxylic acid (10.2 g, 42 mmol), HATU (24 g, 63 mmol) and N,N-diisopropylethylamine (22 ml, 126 mmol) were dissolved in THF (350 ml). The reaction mixture was stirred for 30 min at room temperature, then (R)-1-(4-Fluoro-phenyl)-ethylamine 6.3 ml, 46 mmol) was added. The reaction was stirred overnight at room temperature. LCMS indicated that the reaction was complete, and it was concentrated in vacuo. The concentrate was taken up in 1M NaOH (500 ml) and EtOAc (100 ml) and was stirred for 1 hr. The precipitate that formed was collected by filtration and washed with 1M NaOH:EtOAc (4:1) and dried to give the title compound as a white solid (14.8 g, 97%). LCMS [M+H]=365.3
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]([F:30])([F:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][S:15]([C:18]1[N:28]=[C:21]2[N:22]=[C:23]([CH3:27])[CH:24]=[C:25](O)[N:20]2[N:19]=1)(=[O:17])=[O:16]>C(#N)C>[F:6][C:7]([F:30])([F:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][S:15]([C:18]1[N:28]=[C:21]2[N:22]=[C:23]([CH3:27])[CH:24]=[C:25]([Cl:3])[N:20]2[N:19]=1)(=[O:17])=[O:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2nc(S(=O)(=O)Nc3ccccc3C(F)(F)F)nc2n1
Solvent: CC#N
Product: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3ccccc3C(F)(F)F)nc2n1
Reaction time: 72 h

Procedure:
Phosphorus oxychloride (135 ml, 1.47 mol) was diluted with 335 ml of dry acetonitrile and added to 15 g (40 mmol) of N-(2-trifluoromethylphenyl)-7-hydroxy-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide in a one liter flask and heated to reflux with stirring. After about 3 days, the reaction was found to be complete by thin layer chromatography. Volatiles were removed by evaporation under reduced pressure until the mixture became very viscous and the residue was poured onto about one liter of ice and water with stirring. After about 30 minutes, the solid that formed was collected by filtration, washed with ice water, and dried under reduced pressure at room temperature. It was then dissolved in methylene chloride and the resulting solution dried over magnesium sulfate for about five minutes and filtered. The volatiles were removed from the filtrate by evaporation under reduced pressure to obtain the title compound as a white solid residue. The product, the structure of which was confirmed by NMR analysis, amounted to 13.4 g (85.4 percent of theory).
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[H-].[Na+].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>O1CCCC1>[Si:13]([O:8][CH2:7][C:3]1[CH:2]=[C:1]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
To a solution of 1,3-benzenedimethanol (1 g) in tetrahydrofuran (10 mL) was added sodium hydride (60%, 318 mg) under ice-cooling, and the mixture was stirred for 30 minutes. To the reaction mixture was added tert-butyldimethylsilyl chloride (1.09 g), and the mixture was stirred at room temperature for 4 days. Ice water was added to the reaction mixture, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give the title compound (528 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[CH2:11](Br)[CH:12]=[CH2:13]>>[CH2:11]([NH:1][C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1)[CH2:12][CH3:13]
Reactant: COC(=O)c1cnc(N)s1
Reactant: C=CCBr
Product: CCCNc1ncc(C(=O)OC)s1

Procedure:
Methyl 2-aminothiazole-5-carboxylate, prepared by the procedure described in U.S. Pat. No. 4,001,421, is reacted with allyl bromide using the conditions described in Example 15A. This product is then hydrogenated using the procedure described in Example 15B to give methyl 2-propylaminothiazole-5-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2SC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].C(OCC)(=O)C.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1c[nH]c2c(OCc3ccccc3)cccc12
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Product: c1ccc(COc2cccc3cc[nH]c23)cc1

Procedure:
Wet Raney nickel was added in portions to a stirred refluxing solution of 7-(benzyloxy)-3-(methylthio)indole (4.0 g, 14.9 mmol) in ethyl acetate (100 ml) and ethanol (60 ml) until all the starting material had been consumed (by RP HPLC). The mixture was filtered, the filtrate evaporated and the residue chromatographed on silica in ethyl acetate-hexane (1:8) to give a pale oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][CH3:8])[NH:4][N:3]=1.CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=O>C(O)(=O)C>[CH2:7]([C:5]1[N:6]=[C:2]2[N:1]=[CH:11][CH:12]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:3]2[N:4]=1)[CH3:8]
Reactant: CCc1nc(N)n[nH]1
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: CC(=O)O
Product: CCc1nc2nccc(-c3cccnc3)n2n1
Yield: 67.1 %

Procedure:
A mixture of 1.12 g of 3-amino-5-ethyl-1,2,4-triazole and 1.76 g of 3-dimethylamino-1-(3-pyridyl)-2-propene-1-one in 25 ml of glacial acetic acid was refluxed for six hours and the procedure of Example 1 was continued to give 1.51 g of the desired product as colorless needles, mp 147°-149° C.
Reaction SMILES: O.C(O)(=O)C.Br.[O:7]=[C:8]([OH:20])[C@@H:9]([C@H:11]([C@@H:13]([C@@H:15]([C:17]([OH:19])=[O:18])O)O)O)O>C(O)(=O)C>[C:17]([OH:19])(=[O:18])[CH2:15][CH2:13][CH2:11][CH2:9][C:8]([OH:20])=[O:7]
Reactant: O=C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)O
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCCCC(=O)O
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
20 mg catalyst (1.7% Pt-0.6% Rh/Davisil 635) was dispensed into a 1.2 mL vial. Glacial acetic acid was added followed by a 10% water/acetic acid solution according to Table 1. 50 μL of an acetic acid solution containing 1.2 M HBr and 1.6 M D-glucaric acid was added bringing the final solution volume to 100 μL. The vials were transferred to a pressure reactor which was then sealed, purged with nitrogen and pressurized with hydrogen to 820 psig at room temperature. The reactor was agitated and heated to 160° C. for 90 minutes. After 90 minutes, the reactor was cooled to room temperature, vented, and purged with nitrogen prior to being unsealed. Adipic acid yields were determined by mass spectrometry relative to a d8-adipic acid internal standard.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>C(Cl)Cl>[CH3:14][O:13][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4]2)=[O:12]
Reactant: COC(=O)c1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CCN2C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2,3-dihydro-1H-indole-5-carboxylate HCl salt 55a (64.1 mg, 0.3 mmol), and benzoyl chloride 1t (0.042 mL, 0.36 mmol) in CH2Cl2 (1 mL) was added Et3N (0.13 mL, 0.9 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The resulting mixture was partitioned between CH2Cl2 and H2O. The organic solution was dried over Na2SO4 and concentrated. Purification of the residue by flash column chromatography (silica gel, 10-20% EtOAc/Heptanes) gave 55 g (88 mg). MS m/z (M+H+) 282.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[C:14](O)[CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:19]([O:21]C=C)[CH3:20]>>[CH:19]([O:21][CH2:15][CH:14]=[C:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)=[CH2:20]
Reactant: C=COCC
Reactant: CC(O)=C1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Product: C=COCC=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1.08 g of (1-benzylpiperidin-4-ylidene)ethanol in vinyl ethyl ether (30 ml) was added in a nitrogen atmosphere 0.107 g of mercurous trifluoroacetate. After stirring at room temperature for 18 hours, 10 ml of a 10% aqueous solution of sodium hydroxide was added thereto and the resulting mixture was extracted with n-hexane (50 ml). The organic layer was washed with an aqueous solution of sodium chloride (3×10 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to thereby give 1.153 g of the title compound as a colorless oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:15][C:14](=[O:16])[C:13]([CH:17]([NH:19][C:20](=O)[CH3:21])[CH3:18])=[N:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>ClCCCl>[CH3:18][C:17]1[N:19]=[C:20]([CH3:21])[N:12]2[C:13]=1[C:14](=[O:16])[NH:15][C:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[N:11]2
Reactant: CC(=O)NC(C)c1nnc(-c2ccc([N+](=O)[O-])cc2)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: Cc1nc(C)n2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c(=O)c12
Temperature: 65 °C
Reaction time: 4 h

Procedure:
A solution of 13.76 g (8.13 mmol) of N-{1-[3-(4-nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}acetamide from example 5A in 150 ml of 1,2-dichloroethane is treated with 20.87 g (12.69 ml, 136.11 mmol) of phosphoryl chloride while cooling with an ice bath. The mixture is stirred for 4 h at 65° C. After cooling, it is hydrolyzed using aqueous sodium hydrogencarbonate solution. The solvent of the organic phase is removed in vacuo and the residue is purified by flash chromatography (eluent gradient:dichloromethane/methanol 200:1-100:1-50:1).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].C(O)C.C(=O)(O)[O-].[Na+].[F:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[CH:38][C:37]=1[C:51]1([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH2:54][CH2:53][CH2:52]1>C1(C)C=CC=CC=1>[F:35][C:36]1[CH:41]=[C:40]([C:2]2[N:6]3[C:7]4[CH:19]=[CH:18][CH:17]=[N:16][C:8]=4[NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:5]3=[N:4][C:3]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:39]=[CH:38][C:37]=1[C:51]1([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:59])[CH3:60])[CH2:54][CH2:53][CH2:52]1
Reactant: Cc1ccccc1-c1nc2n(c1Br)-c1cccnc1Nc1ccccc1-2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1nc2n(c1-c1ccc(C3(NC(=O)OC(C)(C)C)CCC3)c(F)c1)-c1cccnc1Nc1ccccc1-2
Temperature: 100 °C
Reaction time: 8 h
Yield: 152.1 %

Procedure:
To a suspension of 3-bromo-2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.06 g, 1 eq.) in a mixture of toluene (0.5 mL), ethanol (0.5 mL), and saturated sodium bicarbonate (0.1 mL) was added tert-butyl (1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (0.088 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.017 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (30 mL). The aqueous phase was extracted with dichloromethane (2×30 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (5% ethyl acetate in dichloromethane) gave tert-butyl (1-(2-fluoro-4-(2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.133 g, 40%). M.p.: 138-140° C.; 1H NMR (DMSO-d6) 400 MHz δ 8.63 (s, 1H), 8.13 (d, J=4.4 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.37-7.26 (m, 2H), 7.25-7.13 (m, 5H), 7.08 (t, J=7.4 Hz, 1H), 6.95 (bs. S, 1H), 6.74 (br. S, 1H), 6.69-6.63 (m, 2H), 2.42-2.28 (m, 4H), 2.08 (s, 3H), 2.04-1.94 (m, 1H), 1.76-1.64 (m, 1H), 1.34-1.10 (m, 9H, rotamers from BOC group); LCMS: 588 [M+H].
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([CH3:16])[CH2:9][C:10]([CH3:15])([N+:12]([O-:14])=[O:13])[CH3:11])(=O)=O.[C:17]([O-:20])(=[S:19])[CH3:18].[K+]>C(#N)C>[C:17](=[O:20])([S:19][CH2:6][CH2:7][N:8]([CH3:16])[CH2:9][C:10]([CH3:11])([N+:12]([O-:14])=[O:13])[CH3:15])[CH3:18]
Reactant: CN(CCOS(C)(=O)=O)CC(C)(C)[N+](=O)[O-]
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC#N
Product: CC(=O)SCCN(C)CC(C)(C)[N+](=O)[O-]
Temperature: 50 °C
Yield: 61.8 %

Procedure:
2-(Methyl(2-methyl-2-nitropropyl)amino)ethyl methanesulfonate (12.0 g, 47.2 mmol) was dissolved into anhydrous acetonitrile (200 mL) and solid potassium thioacetate (5.93 g, 1.1 equiv, 51.9 mmol) was added to flask in one portion. The suspension was heated at 50° C. for 4 h. The red slurry was filtered and the solid washed with ethyl acetate (3×150 mL). The filtrate was concentrated to a red brown oil and purified on an ISCO purification system using a 120 g SiO2 column and the following gradient: isocratic 20% EA in hexanes (5 min) and a gradient to 60% EA in hexanes (15 min). The desired fractions were collected and concentrated to give a red oil (6.83 g, 61.8%). 1H NMR (CDCl3, 400 MHz): δ 1.56 (s, 6H), 2.32 (s, 3H), 2.33 (s, 3H), 2.61-2.65 (m, 2H), 2.89-2.93 (m, 4H). LRMS (ESI+) for C9H18N2O3S (234.1); Found: 235 (MH+).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][N:27]=1)[C:23]#[N:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:24]=2)[CH:25]=[CH:26][N:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccnc(OCc2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccnc(OCc3ccccc3)c2)sc2ccccc12
Yield: 32.1 %

Procedure:
Methyl thiosalicylate (0.59 g, 3.5 mmol) and 2-(benzyloxy)isonicotinonitrile (0.37 g, 1.8 mmol) were dissolved in toluene (2.0 ml). Triethylamine (0.54 ml, 3.9 mmol) was added thereto and the mixture was refluxed for 6 hrs. The reaction mixture was subjected to a silica gel (50 g) column chromatography, eluted with hexane-ethyl acetate (2:1, v/v) and recrystallized from ethanol to give the titled compound (0.20 g, 32%) as white crystals.