Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[CH2:2][CH2:3]C.[Al+3].[Cl-].[Cl-].[Cl-].[CH2:11]([N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13][CH3:14]>C(Cl)Cl>[C:1]([Cl:6])(=[O:5])[CH2:2][CH3:3].[CH2:11]([N:15]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)Cl
Agent: CCCCn1c2ccccc2c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)Cl

Procedure:
46.9 g (0.44 tool) of butyryl chloride are added dropwise to a suspension of 93.3 g (0.7 tool) of AlCl3 in 100 ml of methylene chloride in the course of 30 minutes, while stirring and cooling to -10° to -5°. A solution of 22.3 g (0.1 tool) of N-butylcarbazole in 50 ml of CH2Cl2 is then added dropwise at -10° to -5° in the course of 2 hours. The suspension is stirred at 0° to 20° for 16 hours and then poured onto ice. The emulsion formed is extracted twice with CHCl3 and the extract is washed with water, dried over MgSO4 and evaporated. The crude 3,6-dibutyryl-9-butyl-9H-carbazole is re-crystallized from 80 ml of ethanol. The resulting crystals have a melting point of 107°-109°. 3,6-Dipropionyl-9-butyl-9H-carbazole, which has a melting point of 142°-144° is obtained in an analogous manner from 81.4 g of propionyl chloride and 44.7 g of N-butylcarbazole.
Reaction SMILES: [CH2:1]([O:3][P:4]([O:13][CH2:14][CH3:15])([C:6](=[CH2:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])[CH3:2].C([O-])(O)=[O:17].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[CH2:14]([O:13][P:4]([O:3][CH2:1][CH3:2])([C:6]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:12][O:17]1)=[O:5])[CH3:15]
Reactant: O=C([O-])O
Reactant: C=C(C(=O)OCC)P(=O)(OCC)OCC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1(P(=O)(OCC)OCC)CO1
Reaction time: 6 h

Procedure:
To a solution of 2.36 g (0.01 mole) of ethyl 2-diethoxyphosphinylpropenoate (J. Org. Chem., 43, 1259 (1978)) in 150 ml of methylene chloride is added 50 ml of 0.5 N aqueous NaHCO3 solution. The mixture is stirred rapidly at ambient temperature, while meta-chloroperbenzoic acid (0.01 mole) is slowly added. After stirring for about 6 hours longer, the methylene chloride layer is separated off and is washed with 0.5 N NaOH solution and then with water. It is dried with Na2SO4 and is evaporated to dryness to give ethyl 2-diethoxyphosphinyloxiranecarboxylate as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:18]=1[CH3:34].Cl.O1CCOCC1>CN1C(=O)CCC1>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:19]1[C:18]([CH3:34])=[C:17]([NH:1][C:2]2[CH:9]=[C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Cl
Reactant: N#Cc1ccc(N2CCOCC2)cc1N
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(N2CCOCC2)ccc1C#N

Procedure:
Prepared according to Procedure K, Method 2 using 2-amino-4-morpholinobenzonitrile (82 mg, 405 μmol), 4-chloro-2-(2-fluorophenyl)-3-methylquinoline (110 mg, 405 μmol) and 4N hydrochloric acid solution in dioxane (0.010 mL, 40 μmol) in NMP (0.50 mL) to afford product as a tan solid upon purification by chromatography on silica gel, eluting with EtOAc gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 8.11 (1H, d, J=8.6 Hz), 7.90 (1H, d, J=8.6 Hz), 7.61-7.74 (1H, m), 7.45-7.61 (2H, m), 7.32-7.45 (2H, m), 7.26 (1H, t, J=7.4 Hz), 7.08 (1H, t, J=9.2 Hz), 6.55 (1H, br. s.), 6.31 (1H, dd, J=8.8, 2.5 Hz), 5.76 (1H, br. s.), 3.54-3.73 (4H, m), 2.88-3.11 (4H, m), 2.04-2.23 (3H, m). Mass Spectrum (ESI) m/e=439.1 (M+1).
Reaction SMILES: OC1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C(I)C=CC=1.[F:20][C:21]([F:29])([F:28])[C:22](=O)[CH2:23][C:24](=[O:26])[CH3:25].[NH2:30][C:31]([NH2:33])=[S:32]>C(#N)C>[C:24]([C:23]1[S:32][C:31]([NH2:33])=[N:30][C:22]=1[C:21]([F:29])([F:28])[F:20])(=[O:26])[CH3:25]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: NC(N)=S
Agent: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Solvent: CC#N
Product: CC(=O)c1sc(N)nc1C(F)(F)F
Reaction time: 8 h

Procedure:
Hydroxy(tosyloxy)iodobenzene (78.5 g) was added to a solution of 1,1,1-trifluoropentane-2,4-dione in acetonitrile (500 ml). The mixture was heated under reflux for 45 minutes, then cooled, and thiourea (15.2 g) was added. The mixture was heated under reflux for 4 hours and then left to stand overnight. Evaporation and crystallisation of the residue from dichloromethane gave the title compound.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1C=CC=CC=1>[CH3:21][O:20][C:18]([CH2:17][CH:16]1[C:11]2[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:19]
Reactant: COC(=O)C=Cc1ccccc1N=C=Nc1ccccc1
Reactant: C1CCNCC1
Solvent: c1ccccc1
Product: COC(=O)CC1c2ccccc2N=C(N2CCCCC2)N1c1ccccc1
Reaction time: 2 h

Procedure:
The compound (4) (0.605 g, 2.17 mmol) was dissolved in 20 ml of benzene and piperidine (0.222 g, 2.60 mmol) was gently dropped thereto at a room temperature. The reaction mixture was stirred for 2 hours. After 2 hours, the reaction mixture was washed with water and brine. An organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The reaction mixture was subjected to column chromatography (CH2Cl2:MeOH=10:1) to purify the title compound (6) in the form of a white crystal (0.632 g, 80%) (mp 109° C.).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC=CC=1.[C:22]([NH:30][C:31]1[CH:40]=[C:39]([OH:41])[CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:42]1([CH2:48][CH2:49][CH2:50]O)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:22]([NH:30][C:31]1[CH:40]=[C:39]([O:41][CH2:50][CH2:49][CH2:48][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OCCCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1NC(=O)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCCc2ccccc2)cc1NC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
0.28 mL of 40% diisopropyl azodicarboxylate /toluene was added dropwise to 1 mL of tetrahydrofuran solution containing 0.10 g of methyl 2-(benzamido)-4-hydroxybenzoate, 0.060 mL of 3-phenyl-1-propanol and 0.15 g of triphenylphosphine at room temperature, and stirred at the same temperature for 2 hours and 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was purified wish silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to obtain 45 mg of methyl 2-(benzamido)-4-(3-phenylpropoxy)benzoate as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:4][CH:3]=1.Br[C:22]1[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][N:23]=1.N1C=CC=CC=1C1C=CC=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:22]4[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][N:23]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: Clc1cnc(Br)c(Cl)c1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Cl)cc1Cl
Temperature: 150 °C
Reaction time: 12 h
Yield: 33.5 %

Procedure:
A mixture of 10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (Reference Example 72; 100 mg, 0.34 mmol), 2-bromo-3,5-dichloropyridine (239 mg, 1.03 mmol), copper(I) iodide (65 mg, 0.34 mmol), 2,2′-bipyridyl (106 mg, 0.68 mmol) and cesium carbonate (222 mg, 0.68 mmol) in 1-methyl-2-pyrrolidinone (1.5 mL) was stirred at 150° C. for 12 hr. The mixture was diluted with ethyl acetate, filtered through a pad of celite, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 5-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from n-hexane/ethyl acetate to give the title compound (50 mg, 0.114 mmol, 34%) as a colorless solid.
Reaction SMILES: C[O-].[K+].[CH3:4][O:5]CCOCCN(CCOCCOC)CCOCCOC.[CH2:26]([CH:28]([C:31]1[C:32]2[N:33]([C:38]([C:42]3[S:46][C:45]4[CH:47]=[CH:48][C:49](F)=[CH:50][C:44]=4[C:43]=3[CH3:52])=[C:39]([CH3:41])[N:40]=2)[N:34]=[C:35]([CH3:37])[CH:36]=1)[CH2:29][CH3:30])[CH3:27]>ClCCl.O>[CH2:26]([CH:28]([C:31]1[C:32]2[N:33]([C:38]([C:42]3[S:46][C:45]4[CH:47]=[CH:48][C:49]([O:5][CH3:4])=[CH:50][C:44]=4[C:43]=3[CH3:52])=[C:39]([CH3:41])[N:40]=2)[N:34]=[C:35]([CH3:37])[CH:36]=1)[CH2:29][CH3:30])[CH3:27]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Reactant: COCCOCCN(CCOCCOC)CCOCCOC
Agent: C[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCC(CC)c1cc(C)nn2c(-c3sc4ccc(OC)cc4c3C)c(C)nc12
Reaction time: 0.08 h
Yield: 293.2 %

Procedure:
In an oven dried, nitrogen purged, 3 neck, 50 mL round bottom flask, 0.014 g (0.197 mmol) of potassium methoxide and 0.005 mL (0.013 mmol) of tris[2-(2-methoxyethoxy)ethyl]amine are heated at 150° C. and stirred vigorously for 5 minutes. 0.050 g (0.131 mmol) of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-imidazo[1,2-b]pyridazine is added and the reaction is followed by TLC (2:1 Hexanes/Ethyl Acetate) and MS. After 4 h, the reaction mixture is diluted with 20 mL dichloromethane and 20 mL of water. The layers are separated and the aqueous is extracted 3×50 mL of dichloromethane, dried (MgSO4), and concentrated under vacuum. The crude mixture is purified by chromatography using hexanes:ethyl acetate as a solvent system. Combined fractions to obtain 0.015 g of the title compound, 29% yield. MS, ES+=394.2 (M+1); H1NMR (DMSO-d6) δ 7.863-7.842 (d, J=8.368, 1H); 7.327-7.321 (m, 1H); 7.076-7.049 (m, 1H); 6.991 (s, 1H); 3.857 (s, 3H); 3.094 (m, 1H); 2.477 (s, 3H); 2.350 (s, 3H); 2.180 (s, 3H); 1.853-1.760 (m, 4H); 0.793-0.757 (m, 6H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([N:8]2[C:16](=[O:17])[CH:15]3[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([N:8]2[CH:16]([OH:17])[CH:15]3[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1N1C(=O)C2CCCCC2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(Br)cccc1N1C(=O)C2CCCCC2C1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A suspension of 2-(3-bromo-2-methylphenyl)hexahydro-1H-isoindole-1,3(2H)-dione (Intermediate 3-6, 4.5 g, 13.97 mmol) in methanol (150 mL) was treated with sodium borohydride (2.64 g, 69.8 mmol) and stirred at rt for 4 h. The mixture was concentrated, and the residue was dissolved in DCM, washed with NaHCO3 (aq) and water, and dried and concentrated to provide 2-(3-bromo-2-methylphenyl)-3-hydroxyoctahydro-1H-isoindol-1-one as a yellow solid (3.94 g, 87%). Mass spectrum m/z 324, 326 (M+H)+. Without purification, a portion of this material (1.8 g, 5.55 mmol) was dissolved in DCM (50 mL) and treated with triethylsilane (6.46 g, 55.5 mmol). The solution was treated dropwise at rt with TFA (2.14 mL, 27.8 mmol) and stirred at rt for 30 min. The mixture was concentrated and the residue was dissolved in DCM, washed with NaHCO3 (aq) and water. The organic phase was dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)octahydro-1H-isoindol-1-one (Intermediate 4-1, 1.35 g, 79%). 1H NMR (400 MHz, chloroform-d) δ 7.48-7.53 (1 H, m), 7.06-7.09 (2 H, m), 3.78 (1 H, dd, J=9.5, 5.7 Hz), 3.19 (1 H, dd, J=9.5, 2.4 Hz), 2.64-2.70 (1 H, m), 2.45-2.54 (1 H, m), 2.30 (3 H, s), 2.10-2.17 (1 H, m), 1.80-1.88 (1 H, m), 1.62-1.71 (2 H, m), 1.56-1.62 (1 H, m), 1.40-1.51 (1 H, m), 1.31 (2 H, s). Mass spectrum m/z 308, 310 (M+H)+. Also isolated was 2-(3-bromo-2-methylphenyl)-2,3,4,5,6,7-hexahydro-1H-isoindol-1-one (Intermediate 4-2, 224 mg, 13%). 1H NMR (400 MHz, chloroform-d) δ 7.51-7.55 (1 H, m), 7.05-7.14 (2 H, m), 4.09 (2 H, t, J=1.9 Hz), 2.28-2.37 (4 H, m), 2.28 (3 H, s), 1.73-1.85 (4 H, m). Mass spectrum m/z 306, 308 (M+H)+.
Reaction SMILES: [CH2:1]([Zn]CC)[CH3:2].[Cl:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>>[Cl:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:10])[CH2:1][CH3:2]
Reactant: CC[Zn]CC
Reactant: O=C(CCCl)c1ccccc1
Product: CCC(O)(CCCl)c1ccccc1
Yield: 82 %

Procedure:
Diethylzinc addition to 3-chloropropiophenone (0.5 g, 2.97 mmol) was performed according to general procedure B using 10 mol % of Compound B (162.1 mg). The crude product was filtered through a pad of basic alumina with EtOAc (200 mL) to yield 485 mg of 8 (82% yield, 88% ee) as a colorless oil: [α]D 20=−21.0 (c 3.0, MeOH); 1H NMR (CDCl3, 360 MHz) δ 0.76 (dd, J=7.6, 7.6 Hz, 3H), 1.76-1.90 (m, 2H), 2.25-2.34 (m, 2H), 3.20-3.29 (m, 1H), 3.48-3.60 (m, 1H), 7.20-7.39 (m, 5H) ppm; 13C{1H} NMR (CDCl3, 90 MHz) δ 7.55, 36.08, 40.58, 45.46, 77.00, 125.20, 126.92, 128.45, 144.33 ppm; IR (KBr) 3566, 3462, 3087, 3060, 3027, 2969, 2936, 2879, 1602, 1494, 1446, 1340, 1251, 1173, 1124, 1074, 1055, 1031, 1014, 989, 900, 762, 702, 611 cm-1; HRMS calcd for C11H14Cl (—OH)+: 181.0784, found 181.0789 (chlorine splitting pattern observed).
Reaction SMILES: C(N(CC)CC)C.[O:8]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25]>C(Cl)Cl>[O:8]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:27](=[O:28])[NH:26][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CCCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNC(=O)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
Triethylamine (15 ml, 0.11 mol) was added dropwise under a nitrogen atmosphere to a solution of 4-phenoxyphenol (25.1 g, 0.14 mol) and butyl isocyanate (18 ml, 0.16 mol) in 400 ml of methylene chloride. After the addition, the solution was stirred overnight at room temperature. The solution was extracted with 1 N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give 39.59 g of a tan solid. Recrystallization from diisopropyl ether gave the title compound as a white crystalline solid (21.01 g, 55%), mp 75°-77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:13][C:14]#[N:15]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:7][CH2:13][C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: N#CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCSCc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 100 %

Procedure:
13 ml (15.9 g; 0.1 mol) of 4-chlorobenzylmercaptan and a solution of 4.2 g (0.105 mol) of NaOH in 50 ml of water are mixed whilst cold. Thereafter the mixture is heated to about 60° C. and then 7.5 ml (about 1.2 mols) of chloroacetonitrile are added dropwise at this temperature. At the end of this addition (the temperature is then about 80° C.) the mixture is heated under reflux (100° C.) for 30 to 45 minutes. After cooling, the oil which has formed is extracted with ether and the aqueous phase is discarded. The ether solution is washed with dilute NaOH and then with water until the wash waters have a neutral pH. The ether phase is dried over MgSO4 which is filtered off before the ether is evaporated. 19.7 g of the stated product are collected (yield about 100%, relative to the starting 4-chlorobenzylmercaptan); it is in the form of an oil.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([C:11]#[C:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[CH2:29]([O:31][C:32](=[O:48])[CH2:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1)[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([C:11]#[C:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:37]3[CH:36]=[N:35][N:34]([CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:48])[CH:38]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(C#Cc3ccc4ccccc4n3)cn12
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)Cn1cc(-c2cnc(N3CCOCC3)c3nc(C#Cc4ccc5ccccc5n4)cn23)cn1
Temperature: 80 °C

Procedure:
A mixture of compound 80b (100 mg, 0.230 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-Pyrazole-1-acetic acid ethyl ester (129 mg, 0.460 mmol), dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct (17.0 mg, 0.0230 mmol), and 1M sodium carbonate (1.15 mL, 1.15 mmol) in dioxane (4 mL) under and Argon gas atmosphere was heated to 80° C. for 1 h. After cooling, the reaction mixture was filtered through a pad of diatomaceous earth and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (EtOAc/CH2Cl2; 7:3, v/v) to give compound 80c. Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H25N2O3: 508.2 (M+H). found: 508.5.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].ClC1C2C(=C(C(F)(F)F)C=CC=2)N=CC=1.NC1C(C)=CC=CC=1C(O)=O.S(Cl)(Cl)=O.[CH2:57]([N:60]([CH2:69][CH2:70][CH3:71])[CH2:61][CH2:62][CH2:63][CH2:64][NH:65][CH2:66][CH2:67][CH3:68])[CH2:58][CH3:59]>>[CH2:69]([N:60]([CH2:57][CH2:58][CH3:59])[CH2:61][CH2:62][CH2:63][CH2:64][N:65]([CH2:66][CH2:67][CH3:68])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([CH3:2])[C:4]=1[NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)[CH2:70][CH3:71]
Reactant: Cc1cccc(C(=O)Cl)c1Nc1ccnc2c(C(F)(F)F)cccc12
Reactant: CCCNCCCCN(CCC)CCC
Agent: Cc1cccc(C(=O)O)c1N
Agent: Cl
Agent: FC(F)(F)c1cccc2c(Cl)ccnc12
Solvent: O=S(Cl)Cl
Product: CCCN(CCC)CCCCN(CCC)C(=O)c1cccc(C)c1Nc1ccnc2c(C(F)(F)F)cccc12

Procedure:
3-Methyl-2-(8-trifluoromethyl-4-quinolylamino)benzoyl chloride hydrochloride prepared by the reaction of 4-chloro-8-trifluoromethylquinoline with 2-amino-3-methylbenzoic acid and treatment of the reaction product with thionyl chloride, is reacted with 1-dipropylamino-4-propylaminobutane to afford the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CC=C(c2ccnn2C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCOC(=O)N1CCC(c2ccnn2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product of Step 1 (1.30 g, 4.9 mmol) and 20% Pd(OH)2 on carbon (600 mg) in MeOH (30 mL) was stirred at RT under an N2 atmosphere for 8 h. The mixture was filtered through a celite pad and the pad washed with MeOH (70 mL). To give after concentrating under reduced pressure, the piperidine (1.25 g, 96%). 1H NMR (CDCl3, 360 MHz) δ7.39 (1H, d, J=1.9 Hz), 6.00 (1H, d, J=1.9 Hz), 4.30–4.17 (2H, m), 3.83 (3H, s), 2.90–2.67 (3H, m), 1.95–1.81 (2H, m), 1.65–1.45 (2H, m), 1.48 (9H, s). MS (ES+) C14H23N3O2 requires: 265, found: 266 (M+H+, 65%).
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH2:35][CH3:36])[CH2:3][C:4]1[N:5]=[C:6]([C:9]2([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[CH2:13][CH2:12][CH2:11][N:10]2C(OC(C)(C)C)=O)[NH:7][CH:8]=1>FC(F)(F)C(O)=O>[CH3:1][C:2]([CH3:37])([CH2:35][CH3:36])[CH2:3][C:4]1[N:5]=[C:6]([C:9]2([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[CH2:13][CH2:12][CH2:11][NH:10]2)[NH:7][CH:8]=1
Reactant: CCC(C)(C)Cc1c[nH]c(C2(Cc3ccc(-c4ccc(F)cn4)cc3)CCCN2C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(C)Cc1c[nH]c(C2(Cc3ccc(-c4ccc(F)cn4)cc3)CCCN2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1-carboxylate (45 mg, 0.089 mmol) was dissolved in trifluoroacetic acid (1 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated in vacuo to afford the title compound. 1H NMR (500 MHz, CD3OD) δ 8.48 (d, J=2.5 Hz, 1 H), 8.28 (br s, 1 H), 7.83 (dd, J=8.7, 4.2 Hz, 1 H), 7.79 (d, J=8.0 Hz, 2 H), 7.64 (td, J=8.5, 3.0 Hz, 1 H), 6.97 (d, J=8.0 Hz, 2 H), 6.86 (s, 1 H), 3.45-3.39 (m, 3 H), 3.24-3.17 (m, 1 H), 2.52-2.41 (m, 1 H), 2.45 (s, 2 H), 2.33-2.25 (m, 1 H), 2.22-2.13 (m, 1 H), 1.91-1.82 (m, 1 H), 1.22 (q, J=15.0, 7.5 Hz, 2 H), 0.84 (t, J=7.5 Hz, 3 H), 0.81 (s, 6 H); (M+H) found: 407.
Reaction SMILES: [NH2:1][C:2](=[N:33]C(=O)[O-])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([NH2:32])=[N:30][OH:31])=[CH:25][CH:24]=3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl>C(O)C>[NH2:33][C:2](=[NH:1])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([NH2:32])=[N:30][OH:31])=[CH:27][CH:28]=3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: NC(=NO)c1ccc(OCCCN2CCC(CCCOc3ccc(C(N)=NC(=O)[O-])cc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: N=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=NO)cc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
To an ethanol (5 mL) suspension of 0.50 g of tert-butyl=[1-amino-1-(4-{3-[1-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-4-piperidinyl]propoxy}phenyl)methylidene]carbamate was added 1 mL of hydrochloric acid at room temperature, which was then stirred at the same temperature for 15 hours and 30 minutes. To the reaction mixture was added 4 mL of hydrochloric acid at room temperature, which was then stirred at the same temperature for 2 hours and 30 minutes. The solvent was distilled off under reduced pressure, and water was then added, followed by adjustment to pH 12.5 using a 5 mol/L sodium hydroxide aqueous solution. The precipitate was collected by filtration and washed with water. The resultant solid was dissolved in 1 mol/L hydrochloric acid, followed by distilling off the solvent under reduced pressure before purification using silica gel column chromatography (silica gel: ODS-A from YMC, eluent; water:ethanol=95:5). The eluate was concentrated to about 20 mL, which was then adjusted to pH 12.5 using a 5 mol/L sodium hydroxide aqueous solution. The precipitate was collected by filtration and washed with water to provide 0.17 g of 4-{3-[4-(3-{4-[amino(imino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}-N′-hydroxybenzamidine as white solid form.