Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH2:17]([N:24]1[CH2:29][C:28]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=2)([CH2:30][CH2:31]OS(C)(=O)=O)[CH2:27][O:26][C:25]1=[O:45])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[I-].[K+]>CN(C=O)C>[ClH:43].[C:1]([NH:4][C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:7][N:8]([CH2:31][CH2:30][C:28]2([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=3)[CH2:27][O:26][C:25](=[O:45])[N:24]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:29]2)[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)COC(=O)N(Cc2ccccc2)C1
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)COC(=O)N(Cc3ccccc3)C2)CC1
Product: Cl
Yield: 52.4 %

Procedure:
This compound is prepared by the procedure described in step D of EXAMPLE 1 from 2.77 g of 4-acetamido-4-phenylpiperidine, 1.7 g of the compound obtained in step C of EXAMPLE 1 and 0.61 g of potassium iodide in 10 ml of DMF. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (97/3; v/v) as the eluent. The residue is taken up with a saturated solution of gaseous HCl in ether and the solvent is evaporated off under vacuum to give 0.6 g of the expected product after crystallization from AcOEt. M.p.=168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:31]1[CH:32]=[CH:33][CH:34]=[N:35][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:34]4[CH:33]=[CH:32][CH:31]=[CH:36][N:35]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Brc1cccnc1
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2cc(-c3ccccn3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 90 °C
Yield: 66.2 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (500 mg, 1.1 mmol) which was prepared according to the procedure in Step F of Example 26, 5-bromopyridine (0.21 mL, 2.2 mmol) and cesium carbonate (1.08 mg, 3.3 mmol) in water (3 mL) and N,N-dimethylformamide (10 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (44 mg, 0.06 mmol) was added. The mixture was degassed again and then heated to 90° C. for 2.5 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was partially purified by column chromatography (9:1 hexanes/ethyl acetate to ethyl acetate, then 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to give 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (282 mg, 65%) as a brown oil: ESI MS m/z 387, 389 [M+H]+.
Reaction SMILES: [Zr:1].[O:2]=[Sb:3][O:4][Sb:5]=[O:6]>>[O:2]=[Sb:3][O:4][Sb:5]=[O:6].[OH-:2].[Zr+4:1].[OH-:2].[OH-:2].[OH-:2]
Reactant: [Zr]
Agent: O=[Sb]O[Sb]=O
Product: [OH-]
Product: [Zr+4]

Procedure:
The antimony trioxide composition is prepared by adding an aqueous solution of a zirconium salt to an aqueous slurry of antimony trioxide particles to form zirconium hydroxide therein and to deposit the hydroxide on the surfaces of the antimony trioxide particles, recovering the particles and dehydrating them to form a coating of zirconium hydroxide on the particles, dispersing the hydrous zirconium oxide-coated particles in water, and then adding to the resulting aqueous dispersion a silica sol to deposit amorphous silica on the surfaces of the hydrous zirconium oxide coated antimony trioxide particles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH2:34]=[O:35]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:34][OH:35])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=O
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nnc3n2CCCC3(CO)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reaction time: 1 h
Yield: 13.3 %

Procedure:
To a mixture of 8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (300 mg) in DMF (5 mL) was added sodium hydride (60%, 31.6 mg) under ice-cooling, and the mixture was stirred for 1 hr under a nitrogen atmosphere. Paraformaldehyde (39.6 mg) was added to the reaction mixture, and the mixture was stirred for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (42.5 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:23](=[O:29])[C:24]([O:26]CC)=[O:25])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[C:10]([C:23](=[O:29])[C:24]([OH:26])=[O:25])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccccc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccccc3)cc12
Yield: 62.3 %

Procedure:
{1-Benzyl-5-phenyl-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-5-phenyl-1H-indol-3-yl}(oxo)acetate (0.680 g, 1.77 mmol), and potassium hydroxide (0.322 g, 5.74 mmol) in THF (10 mL) and water (10 mL), following the procedure described in Step 4 of Example 5. Crystallization from acetonitrile, and drying for 3.5 hours at 70° C., yielded the title compound as a yellow solid (0.392 g, 62%), mp: 193-195° C. (dec.). Mass spectrum (+ES, [M+H]+) m/z 356; 1 HNMR (500 MHz, DMSO-d6): δ 13.7-14.2 (br s, 1H), 8.7 (s, 1H), 8.45 (d, 1H, J=0.61 Hz), 7.65 (m, 3H), 7.55 (dd, 1H, J=8.7 Hz and 1.1 Hz), 7.45 (t, 2H, J=7.6 Hz), 7.25-7.35 (m, 6H), and 5.65 ppm (s, 2H).
Reaction SMILES: [C:1]1([C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][NH:3]1)=[O:2].[K].[CH3:13][C:14](C)([O-])[CH3:15].C(Br)C#C.C(O)(=O)C>CN(C)C=O.O>[CH2:15]([N:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1]1=[O:2])[C:14]#[CH:13]
Reactant: CC(C)(C)[O-]
Reactant: O=c1[nH]ccc2ccccc12
Agent: C#CCBr
Agent: [K]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1ccc2ccccc2c1=O
Reaction time: 0.5 h

Procedure:
A solution of 1 g (7 mmol) of isocarbostyril in 40 ml of dimethylformamide was treated with 0.86 g (7.7 mmol) of potassium-tert.-butoxide. After stirring under nitrogen for 30 minutes, 0.7 ml of propargyl bromide was added and stirring at room temperature was continued for 1 hour. The reaction mixture was acidified with acetic acid and diluted with water. The precipitated product was filtered off, washed with water and sucked dry. The residue was purified by chromatography over 30 g of silica gel using 5% (v/v) of ethanol in methylene chloride and crystallization from ether to give colorless crystals of 2-(2-propynyl)-1(2H)-isoquinolinone with m.p. 104°-105°. contains about. 0.125 molar amounts of H2O.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:10])C=O.[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][C:17](=[O:21])N2)=C[CH:13]=1.C(Cl)(=O)C([Cl:25])=O>ClCCl.O>[Cl:25][C:10]1[NH:7][C:6]2[C:15]([C:16]=1[CH:17]=[O:21])=[CH:19][CH:20]=[C:12]([Cl:11])[CH:13]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c(Cl)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
Under nitrogen, 27 ml (292 mmol) of phosphorus oxychloride were added dropwise at 0° C. to 28 ml (366 mmol) of N,N-dimethylformamide in 190 ml of dichloromethane. The mixture was stirred for 2 h at ambient temperature. It was cooled to 0° C. and 24.5 g (146 mmol) of 6-chloro-1,3-dihydro-2H-indol-2-one were added in small portions. The mixture was stirred for 4 h at ambient temperature. It was cooled to 0° C. and 12.7 ml (146 mmol) of oxalyl chloride were added. Next, it was stirred for 12 h at ambient temperature. The mixture was cooled and 250 ml of water were added. The organic phase was decanted and washed with water (3 times). A solid precipitated from the organic phase. It was recovered by filtration and dried under reduced pressure in the presence of phosphorus pentoxide. The aqueous phases were combined and stirred for around 7 h. A solid precipitated from the aqueous phase. It was recovered by filtration and it was also dried under reduced pressure in the presence of phosphorus pentoxide. The two precipitates were combined and 16 g of 2,6-dichloro-1H-indole-3-carbaldehyde were obtained in the form of a white/beige solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[F:59]C1C=C(C=CC=1)C(Cl)=O>>[F:59][C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][CH:5]=1)[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)=[O:8]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccc(F)c4)cc3)cc2C1=O

Procedure:
The compound of example 105 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3-fluorobenzoyl chloride. The compound of example 105 was used directly without isolation for the preparation of compound of example 106.
Reaction SMILES: [CH3:1]N1C2N=CNC=2C(=O)NC1=O.Cl[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19].O=C(C)CCCC[N:28]1[C:37](=[O:38])[C:36]2[N:35]([CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:45])[CH3:44])[CH:34]=[N:33][C:32]=2[N:31]([CH3:46])[C:29]1=[O:30].C[Mg]Cl.[Br-]>O1CCCC1>[OH:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14][N:28]1[C:37](=[O:38])[C:36]2[N:35]([CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:44])([OH:45])[CH3:1])[CH:34]=[N:33][C:32]=2[N:31]([CH3:46])[C:29]1=[O:30]
Reactant: CC(C)(O)CCCCCl
Reactant: CC(=O)CCCCn1c(=O)c2c(ncn2CCCCC(C)=O)n(C)c1=O
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: C[Mg]Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCCC(C)(C)O)c(=O)c2c1ncn2CCCCC(C)(C)O

Procedure:
The same compound was also obtained, inter alia, by a one-stage dialkylation of 3-methylxanthine with twice the molar amount of 1-chloro-5-hydroxy-5-methylhexane or by reaction of 1,7-bis-(5-oxohexyl)-3-methylxanthine with two equivalents of methylmagnesium chloride or bromide in anhydrous tetrahydrofuran.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]3[N:31]=[CH:30][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=3)[CH:17]=2)=[O:13])[NH:3]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]3[N:31]=[CH:30][NH:29][N:28]=3)[CH:17]=2)=[O:13])[NH:3]1
Reactant: O=C(NCc1cccc(OCCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1)c1nc2ccccc2c(=O)[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(NCc1cccc(OCCCOc2nc[nH]n2)c1)c1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
To a suspension of 4-oxo-N-({3-[(3-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}propyl)oxy]phenyl}methyl)-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 86 (0.285 g, 0.430 mmol) in acetonitrile (6 mL) were added trifluoroacetic acid (1.27 mL) and triethylsilane (0.082 mL, 0.516 mmol) at room temperature, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diethyl ether-EtOH to give the title compound as a white powder (0.173 g, 96%).
Reaction SMILES: O1C=CC=C1.[NH:6]([C:16]([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].C(N)(N)=O.[CH2:37]([N:43]=[C:44]=[O:45])[C:38]1[O:42][CH:41]=[CH:40][CH:39]=1>>[CH:22]1[C:21]2[CH:20]([CH2:19][O:18][C:16]([NH:6][CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:44]([NH:43][CH2:37][C:38]3[O:42][CH:41]=[CH:40][CH:39]=3)=[O:45])[C:13]([OH:15])=[O:14])=[O:17])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: O=C=NCc1ccco1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: NC(N)=O
Solvent: c1ccoc1
Product: O=C(NCCCCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NCc1ccco1

Procedure:
After Boc deprotection of the Fmoc-Lys(Boc)-OH, Fmoc-Lys-OH was obtained (FIG. 23, (1)). The furan moiety was coupled to the ε-amine of Fmoc-Lys-OH by ureum formation with furfuryl isocyanate to obtain 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-(3-(furan-2-ylmethyl)ureido)hexanoic acid (FIG. 23, (2)), or by amide formation with pentafluorophenyl-furan-2-carboxylate (FIG. 23, (4)) to obtain 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-(furan-2-carboxamido)hexanoic acid (FIG. 23, (5)). The synthesis was finished with Fmoc deprotection, yielding the amphiphilic products (3) or (6) (FIG. 23) as a white powder. Hence, the furan amino acid of Formula (XId) or the furan amino acid of Formula (XIc) was obtained (FIG. 23, (3) or (6) respectively).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[N:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[N:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1ccc2nccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2nccnc2c1
Reaction time: 0.08 h
Yield: 87 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (147 mg, 0.651 mmol) in dichloromethane (4 mL) was added pyridine (125 μL, 1.55 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-aminoquinoxaline (90 mg, 0.62 mmol) was added. The resulting mixture was stirred for 5 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale yellow solid (180 mg, 87%), single spot at Rf 0.60 (ethyl acetate). mp 166.5-166.9° C., HPLC purity 99+% (tR 2.15 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.77 (1H, d, J=1.7 Hz), 8.74 (1H, d, J=1.7 Hz), 8.06 (1H, d, J=8.2 Hz), 8.00 (1H, d, J=9.2 Hz), 7.66 (1H, d, J=2.5 Hz), 7.56 (1H, d, J=7.9 Hz), 7.50 (1H, dd, J=9.1, 2.6 Hz), 7.28-7.22 (1H, obscured under CHCl3), 2.76 (3H, s). LCMS: 332.24 (M−). FAB-MS (MH+, C15H12ClN3O2S): calcd 334.0417, found 334.0433.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:12]#[N:13])([CH:9]1[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:14]1(=O)[CH2:21]CCCCC[CH2:15]1.C1(C(C)=O)CC1>>[C:1]([NH:5][NH:6][C:7]1([C:12]#[N:13])[CH2:8][CH2:21][CH2:14][CH2:15][CH2:10][CH2:11][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NNC(C)(C#N)C1CC1
Reactant: O=C1CCCCCCC1
Agent: CC(=O)C1CC1
Product: CC(C)(C)NNC1(C#N)CCCCCCC1
Yield: 100 %

Procedure:
1-t-Butylhydrazo-1-cyanocyclooctane was prepared in 100% yield using the same procedure described in Example XIIIB for the preparation of 1-t-butylhydrazo-1-cyano-1-cyclopropylethane, substituting the t-butylhydrazone of cyclooctanone for the t-butylhydrazone of methyl cyclopropyl ketone.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[C:18](Br)[CH:19]=2)[CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Sn](CCCC)(CCCC)[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)CCC>C1(C)C=CC=CC=1.[Pd]>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:19]=2)[CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncc(Br)cc2o1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncc(-c3cccnc3)cc2o1
Yield: 55.6 %

Procedure:
The 2-(1-BOC-2-(S)-pyrrolidinyl)-6-bromofuro[3,2-b]pyridine (0.24g, 0.64 mmol) obtained from Example 46a above was dissolved in toluene (6 mL). Tributyl-3-pyridyltin (0.36 g, 1.3 mmol), palladium (O) tetrakis(triphenyl phosphine) (40 mg) was then added to the toluene solution and the resultant mixture was heated under reflux for 16 h. The desired product was extracted with CH2Cl2, dried over MgSO4 and filtered. Solvent was then removed under reduced pressure and the residue was chromatographed (silica gel: Hexane/EtOAc, 5:1 to EtOAc) to afford an oil (0.13 g, 56%). MS (CI/NH3) m/z: 366 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 1.33, 1.55 (2s, 9H), 1.92-2.38 (m, 3H), 3.43-3.70 (m, 2H), 5.08 (m, 1H), 5.15 (m, 1H), 6.75 (brs, 1H), 7.43 (m, 1H), 7.86 (s, 1H), 7.93 (m, 1H), 8.66 (m, 1H), 8.72 (brs, 1H), 8.89 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH2:15])[C:10]=1[CH2:11][CH3:12].[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH:15][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]=1[CH2:11][CH3:12]
Reactant: O=C(O)c1ccccc1
Reactant: CCc1nn(CCN)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCc1nn(CCNC(=O)c2ccccc2)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
A solution of the amine of Example 43 (98 mg, 0.30 mmol) in dimethylformamide (3.75 ml) was treated with benzoic acid (41 mg, 0.33 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (64 mg, 0.33 mmol) and 4-dimethylaminopyridine (81 mg, 0.66 mmol) and stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure. The residue was partitioned between dichloromethane and saturated sodium hydrogencarbonate solution. The organic extract was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) to afford the title compound (48 mg) as a white solid, m.p. 115-117° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]1.[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[C:20]([CH:30]([F:32])[F:31])[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>CN1CCCC1>[ClH:1].[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]3)[CH2:26][CH2:25]2)[CH:21]=[C:20]([CH:30]([F:31])[F:32])[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=c1cnn(CCCCCl)c(=O)[nH]1
Reactant: CC(C)(C)c1nc(C(F)F)cc(N2CCNCC2)n1
Agent: CN1CCCC1
Product: CC(C)(C)c1nc(C(F)F)cc(N2CCN(CCCCn3ncc(=O)[nH]c3=O)CC2)n1
Product: Cl

Procedure:
2-{4-[4-(2-tert-Butyl-6-difluoromethyl-pyrimidin-4-yl)-piperazin-1-yl]butyl}-2H-[1,2,4]triazine-3,5-dione hydrochloride was prepared from 2-(4-chloro-butyl)-2H-[1,2,4]triazine-3,5-dione and 2-tert-butyl-4-piperazin-1-yl-6-difluoromethyl-pyrimidine by analogy to the process described in example 1 using N-methyl-pyrrolidine as solvent.
Reaction SMILES: [C:1]1([C:14]([OH:16])=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH2:27])[C:22]=1[CH3:23].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:24]2[CH:25]=[C:26]([NH:27][C:14]([C:1]3[C:13]4[NH:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:16])[CH:28]=[CH:29][CH:30]=2)[C:22]=1[CH3:23]
Reactant: O=C(O)c1cccc2c1[nH]c1ccccc12
Reactant: Cc1ncn(-c2cccc(N)c2)c1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ncn(-c2cccc(NC(=O)c3cccc4c3[nH]c3ccccc34)c2)c1C
Reaction time: 20 h

Procedure:
To a suspension of 9H-carbazole-1-carboxylic acid (116 mg) and 3-(4,5dimethylimidazol-1-yl)aniline (103 mg) in dichloromethane (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (158 mg) and 4-dimethylaminopyridine (101 mg), and the mixture was stirred for 20 hours. The mixture was diluted with dichloromethane and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. After trituration with methanol, the residue was collected by filtration and dried to give N-[3-(4,5-dimethylimidazol-1-yl)-phenyl]-9H-carbazole-1-carboxamide (86 mg, 41.1%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[CH3:30][C:31]1[N:32]=[CH:33][C:34]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:35][CH:36]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCCCC4)CC3)cc2n1
Product: Cc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCC(N5CCCCC5)CC4)cc3n2)cn1

Procedure:
1′-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-[1,4′]bipiperidinyl (Example 24) was reacted with 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine in General Procedure A. Purification on silica yielded 132. NMR (CDCl3): 1.62 m, 10H, 5×CH2), 1.70 (m, 2H, CH2), 2.13 (t, 2H, CH2, J=11.07 Hz), 2.36 (m, H, CH), 2.58 (m, 2H, CH2), 2.66 (s, 3H, CH3), 3.06 (d, 2H, CH2, J=11.5 Hz), 3.83 (s, 2H, CH2), 3.90-3.92 (m, 4H, 2×CH2), 4.06-4.08 (m, 4H, 2×CH2), 7.25 (d, H, ArH, J=8.1 Hz), 7.31 (s, H, ArH), 8.58 (dd, H, ArH, J=2.14 Hz, 8.09 Hz), 9.52 (d, H, ArH, J=1.9 Hz). MS: (ESI+): MH+=493.45