Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](Cl)=[O:29]>ClCCl.CCOCC.C(OCC)(=O)C>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:28]([C:24]3[O:23][CH:27]=[CH:26][CH:25]=3)=[O:29])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: O=C(Cl)c1ccco1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1c(C#N)ccc1-c1ccc(NC(=O)c2ccco2)cc1
Reaction time: 16 h
Yield: 28.1 %

Procedure:
5-(4-Aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (98 mg, 0.5 mmol) was dissolved in dichloromethane (2 mL) and triethylamine (87 μL, 0.6 mmol) was added. Furan-2-carbonyl chloride (54 μL, 0.55 mmol) was added and the mixture was stirred 16 hours. The mixture was diluted with 50% ether in ethyl acetate and washed with water, saturated NaHCO3, 2N HCl, brine, dried over MgSO4, and passed through a plug of silica gel. The solution was concentrated to give N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-2-furamide (0.041 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(O)(=O)C(C)(C)C.[OH:27][C:28]([CH:35]1[CH2:40][CH2:39][C:38]([CH3:45])([C:41]([O:43][CH3:44])=[O:42])[CH2:37][CH2:36]1)([C:30]1[S:31][CH:32]=[CH:33][N:34]=1)[CH3:29]>CC(N(C)C)=O.C(OCC)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].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]>[OH:27][C:28]([CH:35]1[CH2:40][CH2:39][C:38]([CH3:45])([C:41]([O:43][CH3:44])=[O:42])[CH2:37][CH2:36]1)([C:30]1[S:31][C:32]([C:2]2[CH:3]=[C:4]([NH:9][C:10]3[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=2)=[CH:33][N:34]=1)[CH3:29]
Reactant: COC(=O)C1(C)CCC(C(C)(O)c2nccs2)CC1
Reactant: Cc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Agent: [Pd]
Agent: CC(C)(C)C(=O)O
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C1(C)CCC(C(C)(O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 25 °C

Procedure:
A solution of N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (41 mg, 0.123 mmol), Cataxium A (8.9 mg, 0.025 mmol), tris(dibenzylideneacetone)dipalladium(0) (5.7 mg, 0.0062 mmol), pivalic acid (0.006 mL, 0.049 mmol) and methyl 4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-1-methylcyclohexanecarboxylate (peak 3) (51.2 mg, 0.370 mmol) in dimethylacetamide (0.55 mL) was heated at 125° C. for 24 hours. The reaction mixture was then allowed to cool to room temperature and diluted with diethyl ether (10 mL), ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The layers were separated and the organic layer was washed with water (3×10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (20-50% ethyl acetate/hexanes) to provide methyl 4-{1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}-1-methylcyclohexanecarboxylate. MS ESI calc'd. for C26H30F3N4O3S [M+H]+ 535. found 535. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=4.9 Hz, 1H), 7.91 (s, 1H), 7.87 (s, 1H), 7.34 (s, 1H), 7.27 (s, 1H), 7.10 (s, 1H), 7.06 (d, J=4.9 Hz, 1H), 3.76 (s, 3H), 3.06 (s, 1H), 2.40 (s, 3H), 1.83-1.66 (m, 6H), 1.65 (s, 3H), 1.50-1.42 (m, 2H), 1.39-1.33 (m, 1H), 1.17 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].F[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.[NH4+].[Cl-]>CS(C)=O>[N+:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: Oc1cccnc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
To a solution of 3-hydroxypyridine (5.01 g, 52.7 mmol) in DMSO (60 mL) was added NaH (1.39 g, 57.9 mmol, 2.31 g of 60% suspended in oil) and stirred for 30 min at RT. To the slurry was added 1-fluoro-3-nitrobenzene (9.66 g, 68.5 mmol) and mixture was heated to 80° C. for 72 h. The mixture was poured into satd NH4Cl solution (200 mL), and extracted with EtOAc (3×125 mL). The combined organic extracts were washed with H2O (75 mL), brine, dried (Na2SO4) and concentrated to yield a crude residue which was purified by column chromatography afford (4.43 g, 39% yield) pure 3-(3-nitrophenoxy)pyridine as a syrup. 1H NMR (400 MHz, Acetone-d6): δ 8.49-8.47 (m, 2H), 8.07-8.05 (m, 1H), 7.85 (t, J=2.4 Hz, 1H), 7.74 (t, J=8.4 Hz, 1H), 7.58-7.53 (m, 2H), 7.51-7.47 (m, 1H); MS (ESI) m/z: 217.0 (M+H+).
Reaction SMILES: N12CCCN=C1CCC[CH2:3][CH2:2]2.[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:28]2[NH:32][N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[N:29]=2)=[N:17][C:18]=1[C:19]1[O:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:22][N:23]=1.ICC>O>[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:28]2[N:32]([CH2:2][CH3:3])[N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[N:29]=2)=[N:17][C:18]=1[C:19]1[O:20][C:21]([C:24]([CH3:26])([CH3:27])[CH3:25])=[N:22][N:23]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n2)CC1
Solvent: O
Solvent: CCI
Product: CCn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 35 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (76 mL, 511.14 mmol) was added to a suspension of tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (150 g, 319.46 mmol) in 2-methylTHF (1.2 L). Iodoethane (46 mL, 575.03 mmol) was added and the mixture was stirred for 16 hours at 35° C. Further iodoethane (46 mL, 575.03 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (76 mL, 511.14 mmol) were added and stirring was continued for 24 hours at 35° C. The mixture was poured into water and the insoluble material was isolated by filtration, washed with water and MTBE and dried in vacuo to afford tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (116 g, 73.0%) as a yellow solid. The filtrate was extracted with DCM and the organic solution was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica using gradient elution (30% MTBE/heptane to 100% MTBE). A second crop of the desired product (12 g, 24.12 mmol, 7.55%), was thus isolated as a yellow solid which was later combined with the first crop: 1H NMR Spectrum: (DMSO-d6) 1.41 (9H, s), 1.44 (9H, s), 1.48 (3H, t), 1.52-1.69 (2H, m), 1.87-2.04 (2H, m), 2.79-3.03 (3H, m), 3.86-4.03 (2H, m), 4.59 (2H, q), 7.89 (2H, s), 8.85 (1H, s); Mass Spectrum [M+H]+=498. THF may also be a suitable solvent for the above reaction.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]1([C@H:16]([CH3:20])[C:17](O)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.CN(C)CCCN=C=NCC.[C:33]([CH2:35][C@@H:36]1[CH2:44][C@@H:43]2[C@@H:39]([CH2:40][NH:41][CH2:42]2)[C@@:38]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[O:52][CH3:53])([OH:45])[CH2:37]1)#[N:34]>ClCCl.O.OC1C2N=NNC=2C=CC=1>[C:33]([CH2:35][C@@H:36]1[CH2:44][C@@H:43]2[C@@H:39]([CH2:40][N:41]([C:17](=[O:18])[C@H:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:20])[CH2:42]2)[C@@:38]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[O:52][CH3:53])([OH:45])[CH2:37]1)#[N:34]
Reactant: C[C@H](C(=O)O)c1ccccc1
Reactant: COc1ccccc1[C@]1(O)C[C@H](CC#N)C[C@H]2CNC[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1[C@]1(O)C[C@H](CC#N)C[C@H]2CN(C(=O)[C@@H](C)c3ccccc3)C[C@H]21
Temperature: 20 °C
Reaction time: 20 h
Yield: 57.4 %

Procedure:
0.87 cm3 of diisopropylethylamine, 0.75 g of (S)-2-phenylpropionic acid, 0.02 g of hydroxybenzotriazole hydrate and 1.05 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to a solution of 1.43 g of (3aS,4S,6S,7aR)-6-cyanomethyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol in 20 cm3 of dichloromethane. The reaction mixture is stirred at 20° C. for 20 hours and then washed twice with 30 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.063 mm, height 32 cm, diameter 2.8 cm), eluting under a pressure of 0.6 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50:50 by volume) and collecting fractions of 25 cm3. Fractions 19 to 35 are concentrated to dryness under reduced pressure (2.7 kPa). 1.20 g of (3aS,4S,6S,7aR)-6-cyanomethyl-4-(2-methoxyphenyl)-2-[(S)-2-phenylpropionyl]perhydroisoindol-4-ol in the form of a thick white foam are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.Br[C:45]1[CH:46]=[N:47][CH:48]=[N:49][CH:50]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:30]=[CH:31][C:32]([C:45]3[CH:46]=[N:47][CH:48]=[N:49][CH:50]=3)=[CH:33][CH:34]=2)=[CH:4][CH:3]=1
Reactant: Brc1cncnc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(ncn4-c4cccc(NS(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cncnc5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of N-(3-{1-(4-chloro-phenyl)-6-oxo-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,6-dihydro-purin-9-yl}-phenyl)-methane sulfonamide (prepared as described in example 26, 0.500 g, 0.809 mmol) in N,N-dimethylformamide (20 mL) is degassed with argon for 0.5 h. Then 5-bromopyrimidine (0.195 g, 1.21 mmol), cesium carbonate (0.527 g, 1.61 mmol), Pd(dppf)2Cl2 (0.059 g, 0.08 mmol) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is heated to 100° C. for 3 h. The reaction mixture is poured into water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to afford N-{3-[1-(4-chloro-phenyl)-6-oxo-2-(4-pyrimidin-5-yl-phenyl)-1,6-dihydro-purin-9-yl]-phenyl}-methane sulfonamide. 1H NMR (DMSO-d6, 400 MHz) δ 10.2 (s, 1H), 9.17 (s, 1H), 9.13 (m, 2H), 8.62 (s, 1H), 7.75 (m, 3H), 7.56 (m, 3H), 7.43-7.50 (m, 5H), 7.25 (d, 1H), 3.05 (s, 3H); LC-MS calculated for C28H20ClN7O3S (M+H+) 570.1, found 569.9.
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[CH3:10][O:11][CH2:12][C:13]([NH:15][C:16]1[C:21]([C:22](=[O:25])[NH:23][CH3:24])=[C:20]([O:26][CH3:27])[C:19]([NH:28][C:29](=O)[CH2:30][O:31][CH3:32])=[C:18]([C:34](=[O:37])[NH:35][CH3:36])[C:17]=1[O:38][CH3:39])=O.[K+].[Br-]>C(OCC)(=O)C.CO>[CH3:32][O:31][CH2:30][C:29]1[N:35]([CH3:36])[C:34](=[O:37])[C:18]2[C:19]([N:28]=1)=[C:20]([O:26][CH3:27])[C:21]1[C:22](=[O:25])[N:23]([CH3:24])[C:13]([CH2:12][O:11][CH3:10])=[N:15][C:16]=1[C:17]=2[O:38][CH3:39]
Reactant: CNC(=O)c1c(NC(=O)COC)c(OC)c(C(=O)NC)c(NC(=O)COC)c1OC
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: COCc1nc2c(OC)c3c(=O)n(C)c(COC)nc3c(OC)c2c(=O)n1C
Temperature: 100 °C

Procedure:
To 100 mL acetic acid and 4 mL concentrated sulfuric acid, was added 1.80 g (4.22 mmol) of 11 and the mixture was heated at 100° C. for 5 hours. After evaporating the solvents down to ca 5 mL, the oily residue was poured over 100 mL of ice water, neutralized with sodium carbonate, and the resulting solution extracted with 3×100 mL portions of chloroform. The combined extracts were evaporated to a small volume, placed on a silica column, and purified by flash chromatography employing ethyl acetate as the eluant. The product fraction was collected and evaporated to dryness. Recrystallization was carried out by redissolving the product in a minimum amount of chloroform followed by addition of hexane: 1.10 g (67%) yield; mp 223°-224° C.; TLC (ethyl acetate/methanol [9:1], Rf =0.22; IR (KBr pellet) 1688, 1614, 1474, 1428, 1375, 1342, 1269, 1097, 1036, 797 cm-1 ; 1H NMR (dimethyl-d6 sulfoxide) δ4.58 (4H, s, methylenes), 3.93, 3.62 and 3.42 (18H, 3×s, N- and O-methyls, no assignments made); mass spectrum (EI mode) m/z 390 (P+). Anal. Calcd for C18H22N4O6. 0.3H2O: C, 54.75; H, 5.74; N, 14.19. Found: C, 54.39; H, 5.63; N, 14.25.
Reaction SMILES: OO.S([O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[Cl:15])(O)(=O)=O.Cl.Cl.[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[NH2:30])[CH2:19][CH2:20][CH3:21].N>O.C(O)C>[Cl:15][C:9]1[C:8](=[O:7])[CH:13]=[CH:12][C:11](=[N:14][C:27]2[CH:28]=[C:23]([O:22][CH2:18][CH2:19][CH2:20][CH3:21])[C:24]([NH2:30])=[CH:25][C:26]=2[NH2:29])[CH:10]=1
Reactant: Nc1ccc(OS(=O)(=O)O)c(Cl)c1
Reactant: CCCCOc1ccc(N)cc1N
Agent: Cl
Agent: N
Agent: OO
Solvent: O
Solvent: CCO
Product: CCCCOc1cc(N=C2C=CC(=O)C(Cl)=C2)c(N)cc1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
26 ml of 6% aqueous hydrogen peroxide solution are added to a solution of 180 mg (0.001 mol) of 4-amino-2-chlorophenol sulfate and 253 mg (0.001 mol) of 4-butoxybenzene-1,3-diamine dihydrochloride in 2 ml of water and 2 ml of ethanol, and the solution is adjusted to pH 9.5 with 20% aqueous ammonia. After stirring for 5 hours at room temperature, the precipitate formed is filtered off, washed with water and dried. A brown powder is obtained.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:23][C:7]2[N:8]([CH2:17][C:18]3[CH:22]=[CH:21][S:20][N:19]=3)[C:9]3[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[CH:13][C:14]=3[C:6]=2[CH2:5]1.C(N(CC)CC)C.N12CCN(CC1)CC2.[CH3:39][N:40]([CH3:45])[S:41](Cl)(=[O:43])=[O:42]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:15]([C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:17][C:18]3[CH:22]=[CH:21][S:20][N:19]=3)[C:7]3[CH2:23][C@H:4]([NH:3][S:41]([N:40]([CH3:45])[CH3:39])(=[O:43])=[O:42])[CH2:5][C:6]=3[C:14]=2[CH:13]=1)#[N:16]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2ccsn2)C[C@H](N)C1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CN(C)S(=O)(=O)N[C@@H]1Cc2c(n(Cc3ccsn3)c3ccc(C#N)cc23)C1
Temperature: 54 °C
Yield: 75.1 %

Procedure:
Mix (R)-2-amino-4-isothiazol-3-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile dihydrochloride salt (1.0 g, 2.72 mmol), triethylamine (0.76 mL, 5.44 mmol), and 1,4-diazabicyclo[2,2,2]octane (0.52 g, 4.63 mmol) in CHCl3 (80 mL) and heat in an oil bath until the internal temperature reaches to 54° C. Add a solution of dimethylsulfamoyl chloride (0.35 mL, 3.26 mmol) in CHCl3 (10 mL) drop wise to the reaction mixture via addition funnel under a nitrogen atmosphere over 30 min. Stir the resulting mixture for an additional hour at 54° C. and then cool to room temperature. Dilute with CH2Cl2 (150 mL), wash the organic layer with saturated NaHCO3, dry (Na2SO4), filter, and concentrate in vacuo. Purify using silica gel chromatography on with EtOAc/hexane (8/2) to yield 0.82 g (75%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.88 (s, 1H), 7.74 (d, J=5.0 Hz, 1H), 7.64 (d, J=5.1 Hz, 1H), 7.38 (d, J=5.0 Hz, 1H), 7.17 (s, 1H), 5.52 (s, 2H), 4.52-4.40 (m, 2H), 3.31-3.18 (m, 2H), 2.62 (s, 6H).
Reaction SMILES: [OH:1][C:2]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][C:16]=2[N+:25]([O-])=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:35]([O:37][CH2:38][C:39](Cl)=O)[CH3:36]>[Pt].C(O)C>[CH2:35]([O:37][CH2:38][C:39]1[N:14]([CH2:13][C:2]2([OH:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH3:36]
Reactant: CCOC(=O)N1CCC(O)(CNc2c([N+](=O)[O-])cnc3ccccc23)CC1
Reactant: CCOCC(=O)Cl
Agent: [Pt]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)OCC)CC1
Reaction time: 2.5 h
Yield: 60.9 %

Procedure:
A mixture of ethyl 4-hydroxy-4-{[(3-nitroquinolin-4-yl)amino]methyl}piperidine-1-carboxylate (4.53 g, 12.1 mmol) and 5% platinum on carbon (0.50 g) in ethanol was hydrogenated on a Parr apparatus at 40 psi (2.8×105 Pa) for 2.5 h. The mixture was filtered through CELITE filter agent and the filtrate was concentrated. The residue was concentrated twice from toluene and once from chloroform to remove the ethanol, then was dissolved in dichloromethane (100 mL). To the solution at 0° C. was added triethylamine (1.86 mL, 13.3 mmol) and ethoxyacetyl chloride (88%, 1.77 g, 12.7 mmol). After 1 h at rt, the solution was concentrated to a yellow foam and ethanol (120 mL) and triethylamine (6 mL) were added. The resulting solution was heated at reflux for 16 h and then concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was washed twice with brine, dried over MgSO4, filtered, and concentrated to a crude yellow oil. The oil was purified by flash chromatography (silica gel, gradient elution with 2-7% methanol/dichloromethane) to provide ethyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate as a yellow foam (3.04 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: C1COCCN1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(N3CCOCC3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (125.5 mg, 0.384 mmol) and morpholine were reacted as starting materials at 100° C. for 15 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow crystalline powder (115.2 mg, 79.5%). Melting point: 188.0-190.3° C. (chloroform-diethylether).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[N:6][CH:7]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:26]1([C:2]2[CH:3]=[C:4]([NH:8][C:9]([N:11]3[C:19]4[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=4)[CH2:13][CH2:12]3)=[O:10])[CH:5]=[N:6][CH:7]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cncc(Br)c1)CC2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cncc(-c3ccccc3)c1)CC2
Yield: 67.7 %

Procedure:
A mixture of 1-(5-bromo-pyrid-3-yl carbamoyl)-5-methoxy-6-trifluoromethylindoline (D14, 208 mg, 0.5 mmol), phenyl boronic acid (300 mg, 2.4 mmol), sodium carbonate (0.32 g, 3 mmol) and tetrakis (triphenylphosphine) palladium (0) (30 mg) in dimethoxyethane-water (5 ml-1 ml) was heated to reflux under argon for 10 h. The cooled reaction mixture was partitioned between ethyl acetate-half saturated brine. The organic extract was dried and evaporated affording a brown solid (0.14 g). Chromatography on silica, eluting with a gradient of 0-5% methanol in ethyl acetate afforded the title compound as a white crystalline solid (100 mg, 48%), m.p. 162-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-:23].[Na+].OO>ClCCl.[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:16][CH2:17][CH2:18][C:19]([NH2:20])=[O:23])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:21][CH:22]=1
Reactant: [OH-]
Reactant: N#CCCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: OO
Solvent: ClCCl
Product: NC(=O)CCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Reaction time: 23 h

Procedure:
A solution of 4-[N,N-Bis-(4-chlorobenzyl)amino]butyronitrile (2.0 g) prepared according to Example 1 in dichloromethane (10 ml) was cooled in ice, then treated with the phase-transfer catalyst nBu4NHSO4 (0.5 g), 20% aq NaOH (3.2 ml ) and 30% H2O2 (4.0 ml ). The mixture was stirred vigorously at 0° for about half an hour, then at room temperature for 23 hours. After dilution with dichloromethane the layers were separated, and the organic phase washed with water and with dil. aq. NaHSO3, then dried (MgSO4) Filtration and evaporation gave a syrup (2.26 g) which was flash-chromatographed on neutral alumina eluted with neat toluene (to remove starting material (0.3 g )) and then with 10% EtOH-toluene to recover the product (1.62 g). Repeat chromatography on silica eluted with 2-5% EtOH-toluene gave the title compound (1.55 g; 73.6%) as a syrup which set solid on standing. The resulting crystals had m.p. 66°-76°.
Reaction SMILES: NCCNC(=O)OCC1C=CC=CC=1.[N:15]([C:18](=[CH:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2)[C:19]([O:21][CH3:22])=[O:20])=[N+]=[N-].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:23]1[C:24]2=[C:25]3[C:29]([CH:30]=[CH:31][C:32]2=[N:15][C:18]=1[C:19]([O:21][CH3:22])=[O:20])=[N:28][CH:27]=[CH:26]3
Reactant: COC(=O)C(=Cc1cccc2[nH]ccc12)N=[N+]=[N-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCCNC(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2c3c(ccc2=N1)=NC=C3
Temperature: 25 °C
Reaction time: 7 h
Yield: 206.8 %

Procedure:
To compound 1 (18.2 mg, 0.03 mmol) in DMF (2 mL) was added 2 (16 mg, 0.036 mmol) and HATU (14 mg, 0.036 mmol) followed by adding DIPEA (19 uL) and the reaction mixture was stirred for 7 hrs at 25° C. The solvent was removed under vacuo and the product was purified by Prep HPLC (SymmetrPrep C18, 7 μm, 19×150 mm column), eluted at 10 ml/min (0.01% TFA in water/acetonitrile) with a gradient: 10% acetonitrile in 5 min, 10% to 50% acetonitrile in 15 min, maintaining 50% acetonitrile in 5 min, 50% to 100% acetonitrile in 5 min, to give 3 (15.8 mg, 53%). MS: calcd for C59H58ClN7O9 (M+H) m/z 1044.4 found 1045.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=1[Cl:12])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccc(Cl)cc1Cl
Yield: 38 %

Procedure:
The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2,4-dichloro phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.26 g, 38%). EI-MS m/z 342 (M+H)+