Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:20])=[O:19])[CH2:14][CH2:13]1)C1C=CC=CC=1.CO.[H][H]>[OH-].[Pd+2].[OH-].O1CCCC1>[C:23]1([CH2:22][CH2:21][S:18]([N:15]2[CH2:14][CH2:13][CH:12]([CH2:11][NH2:10])[CH2:17][CH2:16]2)(=[O:19])=[O:20])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(NCC1CCN(S(=O)(=O)C=Cc2ccccc2)CC1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1

Procedure:
A mixture of [1-(2-phenyl-ethenesulfonyl)-piperidin-4-ylmethyl]-carbamic acid benzyl ester (2.5 g), 20% palladium hydroxide (1 g) on carbon, 200 mL of methanol and 50 mL of tetrahydrofuran were shaken under 50 psi of hydrogen for 2 days at room temperature. The catalyst was filtered off and washed with 250 mL of methanol. Concentration under reduced pressure gave C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine as white solid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[F:7][C:8]([F:12])([F:11])[CH:9]=[CH2:10]>N(C(C)(C)C#N)=NC(C)(C)C#N.C(C1C=CC=CC=1)(=O)CCCCCCC.C1(C)C=CC=CC=1>[F:7][C:8]([F:12])([F:11])[CH2:9][CH2:10][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: C=CC(F)(F)F
Reactant: O=C(O)CCS
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCCCCCC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)CCSCCC(F)(F)F
Temperature: 60 °C
Reaction time: 27 h
Yield: 82.5 %

Procedure:
A 100 mL stainless steel Parr reactor was charged with azobisisobutyronitrile (AIBN, 0.231 g, 1.41 mmol), toluene (45 mL), 3-mercaptopropionic acid (3.40 g, 32.0 mmol), and octanophenone (526.2 mg) as an internal standard and was purged and pressure checked with nitrogen. The reactor was cooled with dry ice and the 3,3,3-trifluoropropene (3.1 g, 32.3 mmol) was condensed into the reactor. The ice bath was removed and the reactor heated to 60° C. and stirred for 27 hours. The internal yield of the reaction was determined to be 80% by use of the octanophenone internal standard. The pressure was released and the crude mixture removed from the reactor. The mixture was concentrated by rotary evaporation and 50 mL of 10% sodium hydroxide was added. The solution was washed with methyl tert-butylether (50 mL) then acidified to pH˜1 with 6 N hydrochloric acid. The product was extracted with 100 mL methyl tert-butylether, dried over magnesium sulfate (MgSO4), filtered, and concentrated to give the crude titled compound as an oil (5.34 g, 26.4 mmol, 83%, 87.5 area % on GC): 1H NMR (400 MHz, CDCl3) δ 2.83 (td, J=7.1, 0.9 Hz, 2H), 2.76-2.64 (m, 4H), 2.47-2.30 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 177.68, 125.91 (q, J=277.1 Hz), 34.58 (q, J=28.8 Hz), 34.39, 26.63, 24.09 (q, J=3.3 Hz); 19F NMR (376 MHz, CDCl3) δ −66.49.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:16]/[C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)/[C:9]#[N:10])=[C:4]([F:11])[CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: O=Cc1cccc(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(F)c1)c1ccc(Cl)cc1F
Yield: 99.3 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (3.27 g, 19 mmol) was reacted with 3-fluorobenzaldehyde (Aldrich) (2.87 g, 23 mmol), methanolic solution (25 wt %) of sodium methoxide (4.83 mL, 21 mmol) in methanol (90 mL) at 50° C. for 3 h to give (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-fluoro-phenyl)-acrylonitrile as a white powder (5.2 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].CCN(CC)CC.N1C=CC=CC=1.[SH2:24].N#N>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4](=[S:24])[NH2:5]
Reactant: N#Cc1c(F)cccc1Cl
Reactant: S
Agent: N#N
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1c(F)cccc1Cl
Temperature: -19 °C
Yield: 71.8 %

Procedure:
2-Chloro-6-fluorobenzonitrile, (99.1%, 62.2 g, 0.40 mol) was weighed into a 1-L three-necked roundbottom flask equipped with a condenser and an overhead electric stirrer, along with Et3N (78 mL, 56.6 g, 0.56 mol) and 180 mL (176.04 g, 2.23 mol) of pyridine. The reactor was purged with a slow stream of N2 and vented to a 13% bleach solution. The stirring solution was cooled to −19° C. in a CCl4/dry ice bath, and H2S gas (33.6 g, 0.99 mol) was sparged below the liquid surface at a rate of 0.4 g/min over a period of 82 min. During the gas addition, the solution temperature rose to −11° C. The yellow-green solution was allowed to gradually warm to 25° C. and stir overnight with a slow N2 purge of the reactor head space into bleach solution. The solution was poured into 1.6 L of ice water, stirred, and the resulting white crystals were collected on a buchner funnel and rinsed with additional water. After 2 h of air drying, the moist filter cake was vacuum oven dried for 5 h at 65° C. to give 54.5 g of 2-Chloro-6-Fluorobenzthioamide (72% wt. % yield), mp 155-160° C., having a GC area % purity of 98.8% and containing 1.2% 2-Chloro-6-fluorobenzonitrile.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[NH2:28])=[CH:18][CH:17]=1.C(O)C.[BH4-].[Na+]>O>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][CH2:10]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1nccn1Cc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccn2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
4-Oxo-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (0.053 mol), 1-[(4-fluorophenyl)methyl]-1H-imidazol-2-amine and titanium(IV)isopropoxyde (0.055 mol) were stirred at 50° C. for 2 hours. Ethanol (350 ml) and sodium borohydride (0.53 mol) were added. The mixture was stirred at RT overnight and water was added. The mixture was filtered over decalite, washed with ethanol/CH2Cl2 and the solvent was evaporated. The residue was taken up in CH2Cl2, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99/1, 98/2, 97/3, 96/4 and 94/6). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE and the precipitate was filtered off and dried, yielding 11.3 g (57%) of 1,1-dimethylethyl 4-[[1-[(4-fluorophenyl)methyl]-1H-imidazol-2-yl]amino]-1-piperidinecarboxylate (intermediate 29).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][CH2:9][C@@H:10]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][C:12]([F:16])([F:15])[CH2:13]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N-:49]=[N+:50]=[N-:51].[Na+]>C(Cl)Cl>[N:49]([CH2:13][C:12]([F:16])([F:15])[CH2:11][C@H:10]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:9][O:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N+:50]=[N-:51]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](COC(=O)OC(C)(C)C)CC(F)(F)CO
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CN(C(=O)OC(C)(C)C)[C@H](COC(=O)OC(C)(C)C)CC(F)(F)CN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a mixture of (S)-tert-butyl 1-(tert-butoxycarbonyloxy)-4,4-difluoro-5-hydroxypentan-2-yl(methyl)carbamate (35.3 g, 0.0956 mol) and lutidine (22.2 mL, 0.191 mol) in DCM (300 mL) was added trifluoromethanesulfonic anhydride (19.3 mL, 0.115 mol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated down. The resulting residue was dissolved in DMF (100 mL) and sodium azide (62.1 g, 0.956 mol) was added. The reaction mixture was stirred at RT overnight. The reaction solution was partitioned between EtOAc and saturated sodium bicarbonate solution. After separating layers, the aqueous layer was extracted further with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated, and the resulting residue was purified by silica gel column (hexanes/EtOAc) to give (S)-tert-butyl 5-azido-1-(tert-butoxycarbonyloxy)-4,4-difluoropentan-2-yl(methyl)carbamate (0.0956 mol, 100%). LRMS (M+Na+) m/z 417.4.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[CH:23]([N:19]1[C:18]([C:12]2[CH:13]=[C:14]3[N:10]([C:9]4[CH:26]=[C:5]([CH:3]5[CH2:2][N:1]([C:27](=[O:29])[CH3:28])[CH2:4]5)[CH:6]=[CH:7][C:8]=4[O:17][CH2:16][CH2:15]3)[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Product: CC(=O)N1CC(c2ccc3c(c2)-n2nc(-c4ncnn4C(C)C)cc2CCO3)C1

Procedure:
Following the procedure for 148, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene was reacted with acetic anhydride to give 149 as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.93 (s, 1H); 7.85 (d, J=2.17 Hz, 1H); 7.27-7.20 (m, 1H); 7.19 (d, J=8.32 Hz, 1H); 6.85 (s, 1H); 5.68-5.59 (m, 1H); 4.59-4.50 (m, 3H); 4.44 (t, J=9.38 Hz, 1H); 4.18-4.11 (m, 1H); 4.13-4.05 (m, 1H); 3.89-3.80 (m, 1H); 3.16 (t, J=5.93 Hz, 2H); 1.91 (s, 3H); 1.57 (d, J=6.62 Hz, 6H). LCMS: RT=9.50 min, M+H+=393
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:5])[O-:4].C[NH3+].Cl[CH:9]([C:13](=[O:15])[CH3:14])[C:10](=O)[CH3:11].CCOCC>CO>[C:13]([C:9]1[S:5][C:3](=[O:4])[N:2]([CH3:1])[C:10]=1[CH3:11])(=[O:15])[CH3:14]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: CNC([O-])=S
Agent: C[NH3+]
Solvent: CO
Solvent: CCOCC
Product: CC(=O)c1sc(=O)n(C)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylammonium N-methylthio-carbamate (13.1 g, 0.105 mol; prepared from methylamine and carbonyl sulfide as described, Y. Gelernt et al. 1974, J. Chem. Soc. Perkin Trans. 1, 2610) was partially dissolved in MeOH (150 mL). 3-Chloro-pentane-2,4-dione (14.9 mL, 0.125 mol) was added drop-wise at room temperature, producing a gradual exotherm to 40° C. After stirring at room temperature for 1 h, the solvent was removed in vacuo. The residue was treated with H2O (50 mL) and was extracted with CH2Cl2 (3×50 mL). The combined organic fractions were washed (brine), dried (Na2SO4), filtered, and evaporated in vacuo to an amber-coloured oil. This was purified by chromatography (300 g SiO2, eluting with 1:1 heptane/Et2O to obtain non-cyclized adduct, then Et2O to obtain 5-acetyl-3,4-dimethyl-3H-thiazol-2-one, which was recrystallized from EtOH as colourless needles (14.2 g). 1H-NMR (CDCl3): δ 2.34 (s, 3H), 2.59 (s, 3H), 3.33 (s, 3H). IR (ATR): 1655 and 1621 cm−1 (CO str).
Reaction SMILES: [S:1]=[C:2]1[NH:14][C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[N:12][C:13]=3[C:4]=2[N:3]1[CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].[OH-].[NH4+].I[CH3:28]>O.C(O)C>[CH3:28][S:1][C:2]1[N:3]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:4]2[C:13]3[N:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCn1c(=S)[nH]c2cnc3cccnc3c21
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nc2cnc3cccnc3c2n1CCNC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
tert-Butyl 2-(2-thioxo-2,3-dihydro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethylcarbamate (31 g, 89.8 mmol) in water (150 mL) and ethanol (150 mL) was treated with ammonium hydroxide (30 mL) and iodomethane (25.5 g, 180 mmol) according to the general method of Part E of Example 22. After three hours, most of the ethanol was removed under reduced pressure, and water (500 mL) was added to the resulting suspension. The mixture was allowed to stand for 30 minutes. A solid was present and was isolated by filtration, washed with water and diethyl ether, and dried under vacuum for three hours to provide tert-butyl 2-[2-(methylthio)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]ethylcarbamate as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[N:62]=[C:61]([N:66]1[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]1)[CH:60]=[CH:59]2>ClCCl>[F:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[N:62]=[C:61]([N:66]1[CH2:67][CH2:68][N:69]([C:19](=[O:20])[CH2:18][O:17][CH:14]3[CH2:15][CH2:16][CH:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:23])([F:24])[F:25])[CH:6]=4)[CH2:12][CH2:13]3)[CH2:70][CH2:71]1)[CH:60]=[CH:59]2
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: Fc1ccc2nc(N3CCNCC3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc3cc(F)ccc3n2)CC1
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl) oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (20 ml) was added EDAC.HCl (79.1 mg, 0.41 mmol), HOBt (55.9 mg, 0.41 mmol), triethylamine (83.7 mg, 0.83 mmol) and 6-fluoro-2-(piperazin-1-yl)quinoline (70.2 mg, 0.30 mmol) at room temperature. After stirred overnight, the reaction mixture was then diluted with dichloromethane (100 ml) and washed with water (2×100 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by a silica gel column with 2% methanol in dichloromethane to afford 1-[4-(6-fluoroquinolin-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (80 mg, 48%); (ES, m/z): [M+H]+ 576.20; 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J=8.8 Hz, 1H), 7.94-7.99 (m, 1H), 7.72-7.78 (m, 1H), 7.31-7.37 (m, 2H), 7.02 (t, J=8.0 Hz, 1H), 6.87 (s, 1H), 6.64 (dd, J=2.4 Hz, 9.2 Hz, 1H), 4.48 (d, J=7.6 Hz, 1H), 4.28 (s, 2H), 3.75-3.81 (m, 7H), 3.41-3.49 (m, 2H), 2.17-2.19 (m, 4H), 1.50-1.58 (m, 2H), 1.28-1.36 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)[CH:5]=[CH:6][CH:7]=1.[N:19]([O-])=[O:20].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[N:19][OH:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nccc(CC(=O)c2cccc(Br)c2)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1nccc(C(=NO)C(=O)c2cccc(Br)c2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
12.75 g (39.5 mmol) C1 were dissolved in a mixture of 173 ml glacial acid, 136 ml tetrahydrofurane and 17 ml water. After cooling to 5° C. a solution of 3.24 g (47.0 mmol) sodium nitrite in 25 ml water was added keeping the temperature between 5° C. and 10° C. The cooling was removed and the mixture stirred for 6 hours at room temperature. After removal of the solvent in vacuo 320 ml water and 320 ml ethyl acetate were added. The pH was adjusted to 8 with 3 N NaOH. The phases were separated and the aqueous layer was extracted with 50 ml ethyl acetate. The combined organic layers were dried over sodium sulphate and the solvent was removed in vacuo. The residue was treated with diethylether, filtered off and dried. Yield: 8.33 g (60%) D1, m.p. 156–158° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:32](Cl)(=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([C:32](=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=3)=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC(=O)Cl
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(C(=O)OCC)cc3)cc2)cc1
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(C(=O)OCC)cc1

Procedure:
The titled compound was prepared following the procedure B using ethyl 4-({4-[(4-butylphenyl)ethynyl]benzyl}amino)benzoate and hexanoyl chloride as a yellow oil (92%). 1H NMR (CDCl3, 300 MHz) δ 8.00 (d, J=8.3 Hz, 2H), 7.41 (m, 4H), 7.14 (m, 4H), 7.03 (d, J=8.7 Hz, 2H), 4.89 (s, 2H), 4.37 (q, J=7.2 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H), 2.06 (t, J=7.5 Hz, 2H), 1.67-1.55 (m, 4H), 1.43-1.10 (m, 9H), 0.91 (t, J=7.2 Hz, 3H), 0.82 (t, J=7.0 Hz, 3H). M+ (ESI): 510.5. HPLC, Rt: 6.14 min (Purity: 98.2%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[Br:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][CH:26]=1>CC(CC)=O.CCOCC>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([CH2:24][Br:23])=[CH:26][CH:27]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: BrCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: CCCc1c(OCc2ccc(CBr)cc2)ccc(C(C)=O)c1O

Procedure:
To a solution of 1-(2,4-dihydroxy-3-propyl phenyl) ethanone (10.0 g; 0.051 m) in dry methylethyl ketone (100 ml) was added dried anhydrous sodium carbonate (27 g; 5 mol. eq) and sodium iodide (0.5 g). To the stirred suspension was then added α,α'-dibromo-p-xylene (13.5 g; 0.051 m) and the suspension gently heated at reflux for five hours. The cooled suspension was evaporated under reduced pressure, the residue dissolved in water and extracted with dichloromethane (×2). The organic extract was washed with aqueous sodium hydroxide (2N), then water, dried over magnesium sulphate, filtered, and evaporated to dryness under reduced pressure to give a yellow solid. The solid was stirred with ether (200 ml) for 1 hour and filtered to remove any disubstituted impurity. The filtrate was evaporated under reduced pressure to leave a yellow solid. The solid was chromatographed on a U30 Sorbsil solumn using dichloromethane to give a white solid; recrystallised from ethanol, m.p. 98°-99° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:47]=[CH:46][C:26]([C:27]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([N:36]3[CH2:41][CH2:40][N:39]([CH2:42][CH:43]4[CH2:45][CH2:44]4)[CH2:38][CH2:37]3)[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:48][CH3:49].C(O)(C(F)(F)F)=O.C1(N2CC(C)(C)C(=O)N(C)C3C=NC(NC4C=CC(C(O)=O)=CC=4OC)=NC2=3)CCCC1>>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:47]=[CH:46][C:26]([C:27]([NH:29][C@H:30]5[CH2:31][CH2:32][C@H:33]([N:36]6[CH2:41][CH2:40][N:39]([CH2:42][CH:43]7[CH2:45][CH2:44]7)[CH2:38][CH2:37]6)[CH2:34][CH2:35]5)=[O:28])=[CH:25][C:24]=4[O:48][CH3:49])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1N
Agent: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C

Procedure:
2-Chloro-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (Intermediate 3) (0.13 g, 0.43 mmol, 1 eq), 4-amino-N-(trans-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (Intermediate 11) (0.26 g, 0.67 mmol, 1.5 eq) and TFA (0.17 mL, 2.2 mmol, 5 eq) in TFE (3 mL) were heated together at 80° C. for 18 hours. Further quantity of Intermediate 6 (0.13 g) was added and the reaction further heated for 48 hours. RM was concentrated in vacuo and the residue was purified by flash column chromatography on silica eluting with 0→20% ammonia/MeOH in DCM gradient followed by preparative HPLC (Preparative—4) then finally preparative RP-HPLC-MS (Preparative—1) to give 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((trans)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (0.03 g, 7%).
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH:23]1([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[N:37]=[CH:36][C:35]([C:38](OC)=[O:39])=[CH:34][N:33]=3)[CH2:28][CH2:27]2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[CH:23]1([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[N:37]=[CH:36][C:35]([C:38]([NH:22][C:19]4[NH:20][N:21]=[C:17]([CH2:16][CH2:15][C:9]5[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=5)[CH:18]=4)=[O:39])=[CH:34][N:33]=3)[CH2:30][CH2:31]2)[CH2:25][CH2:24]1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2CCN(C3CC3)CC2)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN(C5CC5)CC4)nc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.6 %

Procedure:
Trimethylaluminium (2M in toluene, 1.92 mL, 3.85 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (381 mg, 1.54 mmol) and methyl 2-(4-cyclopropylpiperazin-1-yl)pyrimidine-5-carboxylate (404 mg, 1.54 mmol) in toluene (7.7 mL) at 25° C. The resulting solution was stirred at ambient temperature for 18 h and then heated at 60° C. for 2 h. The reaction mixture was quenched with methanol (20 mL) and treated with HCl (2N aqueous solution). The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The impure material was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (100 mg, 14%) as a solid.
Reaction SMILES: [Mg].Br[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]1=[O:19].[NH4+].[Cl-]>C1COCC1>[CH3:11][N:12]1[C:13](=[O:19])[CH2:14][CH2:15][CH2:16][C:17]1([CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:18]
Reactant: CN1C(=O)CCCC1=O
Reactant: BrC=Cc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)CCCC1(O)C=Cc1ccccc1

Procedure:
The Grignard reagent prepared in 300 ml of THF from 24 g (1.0 mole) of magnesium and 42 g (0.30 mole) of β-bromostyrene is decanted from excess metal and added dropwise under nitrogen to a solution of 27 g (0.21 moles) of N-methyl glutarimide at 3°- 5°. After 11/2 hrs. at room temperature, the mixture is treated with 250 ml of saturated NH4Cl solution with cooling. The separated aqueous layer is reextracted and the combined THF extracts washed with salt, dried over MgSO4 and freed of solvent. Product is extracted into hot ether and crystallized on cooling to yield white crystals, mp 108°- 112° C.