Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32](S(C)=O)[C:27]=2[S:26][CH:25]=1)=[O:23].[CH:36]([NH2:39])([CH3:38])[CH3:37]>>[CH:36]([NH:39][C:32]1[C:27]2[S:26][CH:25]=[C:24]([C:22]([NH:21][C:3]3[CH:4]=[C:5]([C:8](=[O:20])[NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[O:23])[C:28]=2[N:29]=[CH:30][N:31]=1)([CH3:38])[CH3:37]
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(S(C)=O)ncnc12
Reactant: CC(C)N
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(NC(C)C)ncnc12

Procedure:
The procedure of Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and isopropylamine to obtain the title compound (see Table 1).
Reaction SMILES: [CH2:1]([C:3]1([C:18]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[N:23](COCC[Si](C)(C)C)[N:22]=2)=[O:19])[CH2:8][CH2:7][CH2:6][N:5]([S:9]([C:12]2[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=2)(=[O:11])=[O:10])[CH2:4]1)[CH3:2].C(O)(C(F)(F)F)=O>>[CH2:1]([C:3]1([C:18]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH:27]([CH3:28])[CH3:29])[NH:23][N:22]=2)=[O:19])[CH2:8][CH2:7][CH2:6][N:5]([S:9]([C:12]2[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=2)(=[O:11])=[O:10])[CH2:4]1)[CH3:2]
Reactant: CCC1(C(=O)Nc2cc(OC(C)C)n(COCC[Si](C)(C)C)n2)CCCN(S(=O)(=O)c2cn(C)cn2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCC1(C(=O)Nc2cc(OC(C)C)[nH]n2)CCCN(S(=O)(=O)c2cn(C)cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
The compound (83 mg, 0.15 mmol) synthesized in (1), TFA (0.9 mL), and distilled water (0.1 mL) were stirred at room temperature for 2 hours. The reaction mixture was diluted with a saturated sodium hydrogen carbonate aqueous solution, and extracted with ethyl acetate. The organic layer was collected, and washed once with saturated brine. The organic layer was then dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the title compound (32 mg, 50%).
Reaction SMILES: [CH3:1][C:2]([O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:5])[C:3]#[CH:4].C([Li])CCC.CN([CH:19]=[O:20])C.OP([O-])(O)=O.[K+]>C1COCC1.C1CCCCC1.CCOCC>[CH3:1][C:2]([O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:5])[C:3]#[C:4][CH:19]=[O:20]
Reactant: C#CC(C)(C)O[Si](C)(C)C
Reactant: CN(C)C=O
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C#CC=O)O[Si](C)(C)C
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
Dissolve 3-methyl-3-trimethylsilyloxy-1-butyne (8.35 g, 53.4 mmol) in THF (200 mL) and cool to 40° C. Add n-butyllithium (26.7 mL of a 2.0 M solution in cyclohexane, 53.4 mmol, 1 eq.) dropwise over a 5 minute period. Stir for 10 min., then add dry DMF (8.27 mL, 7.81 g, 107 mmol, 2 eq.) in one portion. After 30 min., pour into a cooled (0° C.), vigorously stirred mixture of 10% KH2PO4 (290 mL, 213 mmol) and ether (300 mL). Separate the layers and wash the organic layer with water (2×200 mL). Dry (MgSO4), filter, and concentrate to give 9.4 g (94% crude) of a light oil. Use without further purification. TLC: Rf=0.40 (20:1 hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz) δ 9.03 (s, 1H), 1.35 (s, 6H), 0.02 (s, 9H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:12][CH:11]=1>CS(C)=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[CH2:4][C@H:17]2[C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:14][CH:15]=1
Reactant: CON(C)C(=O)/C=C/c1ccc(F)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CON(C)C(=O)[C@@H]1C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
In a 1 L three neck flask, DMSO (100 mL) was rapidly stirred as 60% sodium hydride in mineral oil (4.59 g, 115 mmol) was added in 1.5 g portions. After the foaming subsided, trimethylsulfoxonium iodide (25.2 g, 115 mmol) was added portion wise over a 1 h period, maintaining the temperature below 35° C. The reaction was stirred at rt for 30 min. A soln of (E)-3-(4-fluorophenyl)-N-methoxy-N-methyl acrylamide (8 g, 38.2 mmol) in DMSO (50 mL) was then added dropwise maintaining the temperature below 35° C. After 45 min, the reaction was then slowly quenched with sat'd ammonium chloride (25 mL). The solution was then diluted with EtOAc. The solution was washed with water, dried with brine, dried over magnesium sulfate, and concentrated to give trans-2-(4-fluorophenyl)-N-methoxy-N-methylcyclopropanecarboxamide as a clear oil (8.1 g, 95%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.16-7.08 (m, 2H), 7.05-6.93 (m, 2H), 3.72 (s, 3H), 3.26 (s, 3H), 2.55-2.45 (m, 1H), 1.64 (ddd, J=9.2, 5.1, 4.3 Hz, 1H), 1.34-1.29 (m, 2H). LCMS: M+1=224.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[NH:7][C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].FC(F)(F)C(O)=O>C1COCC1.CC#N.O>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)OCC(=O)N2
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)COc2cc(OC)ccc21
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
A solution of 7-(methyloxy)-2H-1,4-benzoxazin-3(4H)-one (1.42 g, 7.9 mmol) dissolved in 5 mL of anhydrous THF was added to a suspension of sodium hydride (0.349 g of a 60% dispersion in mineral oil, 8.7 mmol) in 10 mL of anhydrous THF at room temperature and stirred for 10 minutes. Then, ethyl bromoacetate (1.06 mL, 9.52 mmol) was added and stirred at room temperature for two hours. HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) showed that all of the starting material (Rt=4.4 min) was gone and that a new peak (Rt=6.5 min) had formed. The reaction was quenched with 5 mL of 4.0M HCl in dioxane. The solvent was removed by rotary evaporation and the residue was adsorbed onto approximately 10 g of silica gel and purified by column chromatography (120 g silica gel 40 um, gradient elution from 100% dichloromethane to 10% methanol/90% dichloromethane over 40 minutes) to give ethyl [7-(methyloxy)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetate (1.35 g, 5.1 mmol, 64%) as a white crystalline solid. MS (ES) m/e 266 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]([OH:15])([C:13]#[CH:14])C.O1CCCC1>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[NH2:1][C:2]1[NH:3][C:4]([C:14]#[C:13][CH:11]([OH:15])[CH3:10])([CH3:9])[CH:5]=[CH:6][N:7]=1
Reactant: C#CC(C)(C)O
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(O)C#CC1(C)C=CN=C(N)N1

Procedure:
A mixture of 10.0 g of 2-amino-4-chloro-6-methylpyrimidine, 8.8 ml of 2-methyl-3-butyn-2-ol, 400 ml of tetrahydrofuran (THF), 0.06 g of copper (I) iodide, 0.5 g of bis(triphenylphosphine)palladium (II) chloride and 20.4 ml of triethylamine was heated overnight at reflux under a nitrogen atmosphere. The reaction mixture was allowed to cool. It was then partitioned between 200 ml of ethyl acetate and 100 ml of sodium bicarbonate. The organic layer was washed successively with 100 ml of water and 100 ml of brine. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was placed on a silica gel dry column and eluted with dichloromethane/ethyl acetate/THF (10:90:0.1). The product band was extracted with THF. The organic extract was concentrated. Trituration of the residue (butyl chloride) gave 4.44 g of the title compound as a solid, m.p. 155°; PMR (90 MHz, CDCl3) δ1.65(s, 6H, CH3), 2.3(s, CH3, 3H), 2.8(s, OH, 1H), 5.2(bs, 2H, NH2), 6.6(s, Het-H, 1H); IR(nujol) 2221(w, C≡C) cm-1.
Reaction SMILES: N([O-])=O.[Na+].N[C@@H:6]([C:11]([OH:13])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9].[BrH:14]>O.C(OCC)C>[Br:14][CH:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:11]([OH:13])=[O:12]
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)CC(Br)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of sodium nitrite (31.55 g) in water (70 ml) was added dropwise to a stirred solution of D-leucine (20 g) in 47% aqueous hydrobromic acid (140 ml)/water (211 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours, then diluted with diethyl ether (600 ml). The organic layer was separated and washed with aqueous sodium metabisulphite (200 ml), dried over sodium sulphate, filtered and the solvent removed under reduced pressure to give 2-bromo-4-methyl-pentanoic acid as a yellow oil (27.6 g) [1H NMR (CDCl3): δ0.93 (d, 3H), 0.98 (d, 3H), 1.75-1.85 (m, 1H), 1.91-1.95 (m, 2H), 4.30 (t, 1H)]. Oxalyl chloride (9.56 ml) was added dropwise to a stirred solution of the 2-bromo-4-methylpentanoic acid (10.7 g) and pyridine (0.1 ml) in dichloromethane (60 ml). The reaction mixture was stirred for 20 hours and the solvent was removed under reduced pressure to give 2-bromo-4-methylpentanoyl chloride (12 g) [1H NMR (CDCl3); δ0.95 (d, 3H), 1.01 (d, 3H), 1.80-2.07 (m, 3H), 4.52 (t, 1H)]. A solution of this 2-bromo-4-methylpentanoyl chloride (12 g) in dichloromethane (40 ml) was added dropwise to a stirred solution of 2,6-dimethoxy-4-methylphenol (9.41 g) and triethylamine (15.6 ml) in dichloromethane (20 ml). The reaction mixture was stirred for 20 hours and was then chromatographed on silica gel, eluting with dichloromethane, to give the title compound as a viscous yellow oil (14.7 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([C@H:11]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)[CH2:12][N:13]([CH3:17])[CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.CN1C[C@@H](C2C=CC3C(=CC=CC=3)C=2)C2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)C1.[Cl:60][C:61]1[N:62]=[N:63][C:64](Cl)=[CH:65][CH:66]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:60][C:61]1[N:62]=[N:63][C:64]([C:7]2[CH:16]=[C:15]3[C:10]([C@H:11]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]=4)[CH2:12][N:13]([CH3:17])[CH2:14]3)=[CH:9][CH:8]=2)=[CH:65][CH:66]=1
Reactant: CN1Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2[C@H](c2ccc3ccccc3c2)C1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[C@H](c2ccc3ccccc3c2)C1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1Cc2cc(-c3ccc(Cl)nn3)ccc2[C@H](c2ccc3ccccc3c2)C1
Temperature: 90 °C
Yield: 45.1 %

Procedure:
A solution of the crude Compound 10 (12.5 g, prepared from 15.1 g of Compound 9 using a similar procedure described earlier for the synthesis of Compound 10), 3,6-dichloropyridazine (5.60 g, 37.6 mmol), and sodium carbonate solution (40 mL. 2M, 80.0 mmol) in DMF (25 mL) was degassed with argon. To this mixture was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (2.6 g, 3.1 mmol). The resulting mixture was degassed with argon and then heated at 90° C. for 3 h. After cooling, the solution was quenched by adding water. The solution was extracted into dichloromethane (3×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (100:0 to 0:100 hexanes/ethyl acetate) provided the Compound 31 as a light-red solid (6.23 g, 51%); 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J=9.0 Hz, 1H), 7.99 (d, J=9.0 Hz, 2H), 7.88-7.83 (m, 4H), 7.79 (s, 1H), 7.50-7.47 (m, 2H), 7.38 (dd, J=8.5, 1.5 Hz, 1H), 7.00 (d, J=0.8 Hz, 1H), 5.00-4.90 (m, 1H), 4.50-4.40 (m, 1H), 4.25-4.15 (m, 1H), 3.60-3.50 (m, 1H), 3.15-3.05 (m, 1H), 2.84 (s, 3H). ESI MS m/z 386 [M+H]+.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[ClH:9].Cl.[NH2:11][CH2:12][C:13]1[O:17][C:16]([C:18]([O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31](=[NH:33])[NH2:32])[CH:27]=3)[CH:22]=2)=[O:19])=[CH:15][CH:14]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[ClH:9].[C:4]([CH2:3][CH2:2][C:1]([NH:11][CH2:12][C:13]1[O:17][C:16]([C:18]([O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31](=[NH:32])[NH2:33])[CH:27]=3)[CH:22]=2)=[O:19])=[CH:15][CH:14]=1)=[O:8])([OH:6])=[O:5]
Reactant: O=C(O)CCC(=O)O
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)o3)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)CCC(=O)O)o3)ccc2c1
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
To 22.3 g of succinic acid, 24.0 g of 6-amidino-2-naphthyl 5-aminomethylfuran-2-carboxylate dihydrochloride and 790 mg of DMAP was added 240 ml of pyridine, and the mixture was stirred while cooling with ice. After 10 minutes, 25.9 g of DCC was added and the mixture was stirred for 3 hours while cooling with ice and then for 16 hours at room temperature. The precipitate was filtered off, and the filtrate was added in small portions into 2 l of ether and stirred at room temperature for 3 hours. After removing the supernatant by decantation, 1 l of acetone was added to the residue and stirred for 3 hours. The precipitate was collected by filtration to obtain 24.0 g of the intended product.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C1(NC2CCCCC2)CCCCC1>>[F:28][C:16]([F:15])([F:27])[C:17]1[CH:18]=[CH:19][C:20]([S:23]([O:7][CH2:6][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=[CH:9][C:8]=2[N+:12]([O-:14])=[O:13])(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1CO
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: C1CCC(NC2CCCCC2)CC1
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1COS(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 37.8 %

Procedure:
The procedure of Example 11 was employed except that the reagents were 2.00 g of 2,6-dinitrobenzyl alcohol, 2.71 g of 4-(trifluoromethyl)benzenesulfonyl chloride and 2.2 mL of dicylohexylamine. The crude product was recrystallized using carbon tetrachloride/chloroform to give 1.55 g (38% yield) of white crystals.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:16]([N:26]1[CH2:33][CH2:32][CH2:31][C@@H:27]1[C:28](O)=[O:29])([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:28](=[O:29])[C@H:27]3[CH2:31][CH2:32][CH2:33][N:26]3[S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@@H]2C(=O)O)cc1
Reactant: c1ccc(-c2c[nH]c3ccccc23)cc1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@@H]2C(=O)n2cc(-c3ccccc3)c3ccccc32)cc1

Procedure:
condensing a 3-phenyl indole with an N-tosyl-D-proline to form a 3-phenyl-1-(N-tosyl-D-prolyl) indole,
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3Br)[C:12](=[O:22])[NH:11][C:10](=[O:23])[CH:9]=2)[CH2:3]1.[I:24]C1C=CC=CC=1CCl>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[I:24])[C:12](=[O:22])[NH:11][C:10](=[O:23])[CH:9]=2)[CH2:3]1
Reactant: N[C@@H]1CCCN(c2cc(=O)[nH]c(=O)n2Cc2ccccc2Br)C1
Reactant: ClCc1ccccc1I
Product: N[C@@H]1CCCN(c2cc(=O)[nH]c(=O)n2Cc2ccccc2I)C1

Procedure:
The title compound was prepared by the procedure described in the preparation of compound 8, except that 2-iodobenzyl chloride was used as the benzylating reagent. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.76 (d, J=7.6 Hz, 1H), 7.21 (t, J=7.3 Hz, 1H), 6.89 (t, J=7.2 Hz, 1H), 6.79 (d, J=7.3 Hz, 1H), 5.26 (s, 1H), 4.79-4.92 (ABq, J=34.1, 6.7.0 Hz, 2H), 3.27 (m, 1H), 3.13 (s, 1H), 2.85 (d, J=11.6 Hz, 1H), 2.70 (m, 1H), 2.41 (m, 1H), 2.02 (m, 1H), 1.60 (m, 1H), 1.45 (m, 2H). MS (ES) [m+H] calc'd for C16H20IN4O2, 427.1; found, 427.1.
Reaction SMILES: Br[C:2]1[C:3]([CH2:22][OH:23])=[C:4]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH:18]4[CH2:20][CH2:19]4)[CH:14]=3)[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH3:24][N:25]1[C:30]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[O:39])=[CH:34][CH:33]=2)=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][C:26]1=[O:55].C(Cl)(Cl)Cl.O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O>[CH:18]1([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:21])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:28]4[CH:29]=[C:30]([NH:31][C:32]5[CH:37]=[CH:36][C:35]([C:38]([N:40]6[CH2:41][CH2:42][O:43][CH2:44][CH2:45]6)=[O:39])=[CH:34][CH:33]=5)[N:25]([CH3:24])[C:26](=[O:55])[CH:27]=4)[C:3]=2[CH2:22][OH:23])[CH2:17][CH2:16]3)[CH2:20][CH2:19]1
Reactant: O=C1c2ccc(C3CC3)cc2CCN1c1cccc(Br)c1CO
Reactant: Cn1c(Nc2ccc(C(=O)N3CCOCC3)cc2)cc(B2OC(C)(C)C(C)(C)O2)cc1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(Nc2ccc(C(=O)N3CCOCC3)cc2)cc(-c2cccc(N3CCc4cc(C5CC5)ccc4C3=O)c2CO)cc1=O
Yield: 53.5 %

Procedure:
To a flask charged with 2-(3-bromo-2-hydroxymethyl-phenyl)-6-cyclopropyl-3,4-dihydro-2H-isoquinolin-1-one (3.70 g, 9.9 mmol), 1-Methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (4.38 g, 9.9 mmol), Pd2 (dba)3.CHCl3 (229 mg, 0.25 mmol), 2-Dicyclohexylphosphino-2′,4′,6′-Tri-i-Propyl-1,1′-Biphenyl (238 mg, 0.50 mmol), and K3PO4 hexahydrate (7.5 g, 20 mmol) was added 40 mL of 4:1 dioxane:water and the mixture heated to reflux for 4 h, cooled and filtered over Solka-Floc®, rinsing with ethyl acetate. Partitioned and washed the organic phase with water and brine. Dried over sodium sulfate, filtered and concentrated to afford a dark oil. Purification by silica gel chromatography (methylene chloride/methanol) afforded 3.2 g of 6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-2-oxo-1,2-dihydro-pyridin-4-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one as a colorless solid. MS (ESI) 606.1 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8](OCC)=[O:9].CC(C)([O-])C.[K+:18]>C(OC(C)C)(C)C>[Cl:1]/[C:2](/[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:8]/[O-:9].[K+:18]
Reactant: CCOC(=O)CCl
Reactant: CCOC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Product: CCOC(=O)/C(Cl)=C\[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
A mixture of ethyl 2-chloroacetate (220.8 g; 1802 mmol) and ethyl formate (133.5 g; 1802 mmol) was added slowly to a suspension of potassium t-butoxide (202.2 g; 1802 mmol) in diisopropyl ether (2000 mL) at 0° C. (maintaining the temperature <20° C.) with mechanical stirring. The mixture was stirred at ambient temperature for 24 hours. The solids were collected by filtration and washed with diisopropyl ether (500 mL) and acetonitrile (2×1500 mL). The material was dried under vacuum to give the product (270 g) which was used without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]2)=[CH:4][CH:3]=1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.CN[C@@H]1CCCC[C@H]1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[N:15]1([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]3)=[CH:4][CH:3]=2)[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: OC1CCCN(c2ccc(I)cc2)C1
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: OC1CCCN(c2ccc(-n3cncn3)cc2)C1
Temperature: 110 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a mixture of 1-(4-iodophenyl)piperidin-3-ol (920 mg, 3.03 mmol), 1H-1,2,4-triazole (272 mg, 3.95 mmol), (trans)-N1,N2-dimethylcyclohexane-1,2-diamine (43.2 mg, 0.303 mmol), K3PO4 (1288 mg, 6.07 mmol) and copper(I) iodide (28.9 mg, 0.152 mmol) in DMF (4 mL) was bubbled with Argon for 2 min. Then the reaction was stirred at 110° C. under Argon for 16 hrs. The reaction was diluted water and extracted with EtOAc (2×50 ml). Combined EtOAc extracts were washed with water (30 ml) and saturated aqueous NaCl (30 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give product 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperidin-3-ol (453 mg, 1.854 mmol, 61.1% yield) as a foam. Anal. Calcd. for C13H16N4O m/z 244.2, found: 245.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[CH3:20])=[O:14])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[O:14][C:13]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[CH3:20])=[N:12][N:11]=2)[C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: Cc1ccsc1C(=O)NNC(=O)c1nc(Br)cnc1N
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccsc1-c1nnc(-c2nc(Br)cnc2N)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
To a suspension of 3-amino-6-bromo-N′-(3-methylthiophene-2-carbonyl)pyrazine-2-carbohydrazide (7.85 g, 22.04 mmol) in anhydrous acetonitrile (117.8 mL) cooled in an ice bath was added DIPEA (8.546 g, 11.52 mL, 66.12 mmol) followed by dibromo(triphenyl)phosphorane (12.09 g, 28.65 mmol) portionwise. The resulting suspension was stirred at room temperature for 30 min and the precipitate isolated by filtration and washed with acetonitrile to give the product as a yellow solid (4.42 g, 52% yield); 1H NMR (400 MHz, DMSO) d 2.64 (s, 3H), 7.21 (d, 1H), 7.91 (3H, m) and 8.44 (s, 1H) ppm; MS (ES+) 340.04