Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH2:18]([C:20]([OH:25])([CH2:23][CH3:24])[C:21]#[CH:22])[CH3:19].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:18]([C:20]([OH:25])([CH2:23][CH3:24])[CH2:21][CH2:22][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1)[CH3:19]
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC(O)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(O)(CC)CCc1cccc(CCCNC(=O)C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To a degassed solution of N-(3-(3-bromophenyl)propyl)-2,2,2-trifluoroacetamide (10) (0.930 g, 3 mmol) and 3-ethylpent-1-yn-3-ol (11) (0.670 g, 6 mmol) in triethylamine (4 mL) and DMF (12 mL) was added PdCl2(PPh3)2 (0.053 g, 0.075 mmol), P(o-Tol)3 (0.046 g, 0.15 mmol), and CuI (0.014 g, 0.075 mmol). The resulting mixture was degassed and stirred under argon at 90° C. for 6 h. The mixture was cooled to room temperature then concentrated under reduced pressure and diluted with EtOAc (100 mL) and water (70 mL). After vigorous shaking, the layers were separated. The organic layer was treated with charcoal, dried over MgSO4, filtered, and evaporated under reduced pressure. Purification by flash chromatography (7 to 60% EtOAc-hexanes gradient) gave N-(3-(3-(3-ethyl-3-hydroxypentyl)phenyl)propyl)-2,2,2-trifluoroacetamide (12) as a yellow oil. Yield (0.663 g, 65%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.17-7.28 (m, 4H), 3.16 (q, J=7.2 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.76 (quint, J=7.2 Hz, 2H), 1.53-1.67 (m, 4H), 0.97 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:18]=2)[NH:15][C:14]([C:27]([OH:29])=O)=[CH:13]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.C[N:34](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N>O.CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:18]=2)[NH:15][C:14]([C:27]([NH2:34])=[O:29])=[CH:13]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
A mixture of 5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-pyran-4-ylmethoxy)-1H-indole-2-carboxylic acid (1.0 g), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (0.9 g), 1-hydroxybenzotriazole (0.6 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 15 min. 28% Aqueous ammonia solution (0.8 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2.5 hr. Water was added to the reaction solution, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude product was crystallized from a mixed solvent of ethanol-diethyl ether, and the obtained crystals were washed with diethyl ether to give the title compound (0.8 g, yield 83%) as colorless crystals. MS 445 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5](Cl)=[N:6][CH:7]=1.O.[NH2:21][NH2:22].O.[O:24]1[CH2:29]COCC1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]2[N:6]([C:29](=[O:24])[NH:21][N:22]=2)[CH:7]=1
Reactant: NN
Reactant: Cc1c(Br)cnc(Cl)c1-c1cccc(C(F)(F)F)c1
Reactant: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Br)cn2c(=O)[nH]nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 120 h

Procedure:
A solution of 5-bromo-2-chloro-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridine (Int. 14, 176 mg, 0.503 mmol) and hydrazine hydrate (2.5 mL, 52 mmol) in dioxane (5 mL) was heated at 90° C. for 7 hrs. A further quantity of hydrazine hydrate (2.5 mL) was added and the reaction mixture heated at 90° C. for 18 hrs and then at 100° C. for 5 days. The reaction mixture was cooled then poured into water (15 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo to afford a yellow solid. The solid was dissolved in THF (2 mL) and then N,N′-carbonyldiimidazole (375 mg, 2.31 mmol) was added and the reaction mixture stirred at RT for 22 hrs before being concentrated in vacuo. The resultant residue was purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in cyclohexane to give the title compound as a tan solid (184 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[C:16]1[N:17]([CH3:22])[N:18]=[CH:19][C:20]=1[Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:31]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[O:32])=[CH:11][C:10]=1[C:16]1[N:17]([CH3:22])[N:18]=[CH:19][C:20]=1[Br:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCc1ccccc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(F)cc2)ccc1OCc1ccccc1
Yield: 22.2 %

Procedure:
4-Benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (0.031 g, 0.09 mmol) was treated with 4-fluorophenyl isocyanate (0.013 g, 11.0 μL, 0.10 mmol, 1.1 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 62 (0.011 g, 0.02 mmol, 26%) as a white solid. LCMS m/z (%)=511 (M+H79Br, 82), 513 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.12 (s, 2H), 7.66 (dd, J=2.6, 8.9 Hz, 1H), 7.54 (dd, J=4.8, 9.0 Hz, 2H), 7.50 (s, 1H), 7.47 (d, J=2.6 Hz, 1H), 7.25-7.36 (m, 5H), 7.22 (d, J=8.9 Hz, 1H), 7.04 (t, J=8.8 Hz, 2H), 5.13 (AB quartet, J=12.0, 24.4 Hz, 2H), 3.69 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][Cl:10])[N:3]=1.Cl.[CH:12]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][O:14][CH2:13]2.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([N:19]2[CH:12]3[CH2:18][CH2:17][CH:16]2[CH2:15][O:14][CH2:13]3)[CH:5]=[C:4]([CH2:9][Cl:10])[N:3]=1
Reactant: ClCc1cc(Cl)nc(Cl)n1
Reactant: C1CC2COCC1N2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1cc(N2C3CCC2COC3)nc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
A flask was charged with 2,4-dichloro-6-(chloromethyl)pyrimidine (prepared as reported in Bioorg. Med. Chem., 2002, 10, 525), 2.40 g, 12.15 mmol) in dichloromethane (30 mL) to give a yellow solution. 3-Oxa-8-azabicyclo[3.2.1]octane, HCl (33, 1.818 g, 12.15 mmol) and triethylamine (3.56 ml, 25.5 mmol) in dichloromethane (30 mL) were added slowly over 10 minutes, and the resulting solution was allowed to stir at room temperature for 16 hours, then concentrated. The crude product was added to a silica gel column and eluted with 0-40% ethyl acetate in hexanes to provide 8-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (2.30 g, 69%) as an off-white solid. HRMS; [M+H]+ Obs'd=274.0510, [M+H]+ Calc'd=274.0508
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13](#[N:17])[CH2:14][C:15]#[N:16].C1COCC1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[OH:9][C:8]([C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[C:14]([C:13]#[N:17])[C:15]#[N:16]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: N#CCC#N
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: N#CC(C#N)=C(O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
4-Nitrobenzoyl chloride (93 g, 0.50 mol) and malononitrile (33 g, 0.50 mol) were dissolved in toluene (400 mL) and THF (70 mL) in a flask equipped with an addition funnel, a thermometer, a stir bar, and argon atmosphere. The flask was immersed in a −30° C. bath. When the internal temperature reached −10° C., DIPEA (129 g, 1.0 mol) in 300 mL of toluene was added dropwise over 40 min. After an additional 1 hr, the bath was removed. After ca. 14 hr, the mixture had 2 layers. The bottom layer was concentrated in vacuo, dissolved in 400 mL of EtOAc, washed with 10% aqueous citric acid (2×250 mL), dried over Na2SO4, and concentrated in vacuo. The residue was mostly dissolved in THF (100 mL) and left 30 min in a freezer. The resulting solid was collected with the aid of additional freezer-cold THF and pressed well with rubber dam. The isolated solid (60 g) was suspended in 1 M H2SO4, collected, pressed, and washed with water. After drying, the solid weighed 36 g. This solid was dissolved in EtOAc (400 mL), washed with 1 M H2SO4 (200 mL) and water (200 mL), filtered through phase separation paper, and concentrated. The solid residue was reconcentrated successively from dichloromethane and toluene and dried at high vacuum. At this stage, 25 g were isolated. The HPLC purity was 94%. Analysis of a 60 MHz NMR spectrum showed about 18 mol % DIPEA. The material was used in the next step without further purification. Another 15 g portion of solid of 95% HPLC purity but containing 30 mol % DIPEA was eventually isolated from the THF filtrate. This material was set aside. The estimated overall yield of the reaction was about 42% NMR (60 MHz) (CDCl3) δ 8.0 (AB, 4H)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1.[CH3:10][N:11]1[C:15](CCCC(Cl)=S)=[N:14][N:13]=[N:12]1.[C:22](=[S:24])=S>>[CH3:10][N:11]1[C:15]([S:24][CH2:22][CH2:8][CH2:7][C:6]([C:6]2[O:5][CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:14][N:13]=[N:12]1
Reactant: S=C=S
Reactant: Cn1nnnc1CCCC(=S)Cl
Reactant: c1ccoc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cn1nnnc1SCCCC(=O)c1ccco1

Procedure:
Aluminum chloride (4 g) is suspended in carbon disulfide (20 ml) and furan (1.5 g) is added to the suspension. 4-(1-Methyl-1,2,3,4-tetrazol-5-yl)thiobutyryl chloride (4.4 g) added dropwise to the mixture with stirring under ice-cooling, and the mixture is stirred at the same temperature for 1 hour. The reaction mixture is poured into hydrochloric acid-ice and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography (Wakogel C-200, eluting agent, chloroform), the eluate is recrystallized from hexane-ether to give 1-methyl-5-[3-(2-furoyl)propyl]thio-1,2,3,4-tetrazole (0.8 g) as colorless needles, m.p. 41°-42° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][O:7][C:6]=2[CH:13]=1.[Br:14]Br>CCOCC>[Br:14][CH:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:13]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[C:11]1=[O:12]
Reactant: O=C1CCCOc2cc(Br)ccc21
Reactant: BrBr
Solvent: CCOCC
Product: O=C1c2ccc(Br)cc2OCCC1Br
Temperature: 25 °C
Yield: 102.5 %

Procedure:
To a stirred solution of 8-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (3.10 g; 12.8 mmol) in Et2O at 0° C. was added Br2 (625 μl; 12.2 mmol) and the reaction mixture was allowed to warm to r.t. over 2 h. Volatiles were evaporated and the residue purified by flash column chromatography (0-20% EtOAc in hexanes) to give 4,8-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one as a colorless solid (4.0 g, 96% yield). 1H NMR (400 MHz, CDCl3) δ 7.18-7.21 (m, 2H), 7.55 (d, J=8.0, 1H), 4.87 (app. t, J=5.2, 2H), 4.33-4.39 (m, 1H), 4.09-4.16 (m, 1H), 2.78-2.91 (m, 1H), 2.40-2.49 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:26])[C@H:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:3][CH:2]=1.[H-].[Na+].[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[N+:37]([O-:39])=[O:38]>CS(C)=O>[ClH:29].[ClH:29].[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:26])[C@H:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:32]3[C:31]([N+:37]([O-:39])=[O:38])=[CH:30][CH:35]=[C:34]([Cl:36])[CH:33]=3)=[CH:21][CH:20]=2)[NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)Nc1ccncc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Oc2cc(Cl)ccc2[N+](=O)[O-])cc1)C(=O)Nc1ccncc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 151.6 %

Procedure:
To a solution of N-(t-butyloxycarbonyl)-4-hydroxy-L-phenylalanine 4-pyridylamide (5.35 g) in dimethyl sulfoxide (100 ml) was added oily sodium hydride (0.62 g), followed by stirring at room temperature for 30 minutes. Thereafter, 2,4-dichloronitrobenzene (2.88 g) was added and stirred at room temperature for 10 hours. After a conventional post-treatment, N-(t-butyloxycarbonyl)-4-(3-chloro-6-nitrophenoxy)-L-phenylalanine 4-pyridylamide dihydrochloride (6.66 g) was obtained. The above compound (I) (6.50 g) was allowed to react with 4N-hydrogen chloride/dioxane solution (50 ml) to obtain 4-(3-chloro-6-nitrophenoxy-L-phenylalanine 4-pyridylamide dihydrochloride, which was further allowed to react with trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarboxylic acid mixed acid anhydride obtained in Example 5 to obtain N-[trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarbonyl]-4-(3-chloro-6-nitrophenoxy)-L-phenylalanine 4-pyridylamide (II) (7.16 g). The above compound (II) (7.00 g) was allowed to react with 4N-hydrogenn chloride/dioxane solution (150 ml) to obtain N-(trans-4-aminomethylcyclohexylcarbonyl)-4-(3-chloro-6-nitrophenoxy)-L-phenylalanine 4-pyridylamide (6.06 g).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([C:6]2[S:10][C:9]([C:11]3[S:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][CH:7]=2)[S:4][CH:5]=1.ClS([N:20]=[C:21]=O)(=O)=O>C(Cl)Cl>[C:21]([C:14]1[S:15][C:11]([C:9]2[S:10][C:6]([C:3]3[S:4][CH:5]=[CH:1][CH:2]=3)=[CH:7][CH:8]=2)=[CH:12][CH:13]=1)#[N:20]
Reactant: c1csc(-c2ccc(-c3cccs3)s2)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Reaction time: 2 h

Procedure:
To a solution of α-terthienyl (2.46 g, 0.010 m) in methylene chloride (20 ml), was added chlorosulfonyl isocyanate (1.75 ml) in methylene chloride (15 ml). A yellow solid separated almost at once. The reaction mixture was stirred for 2 h and left overnight. Dimethyl formamide (5.0 ml) was added to the ice-cold reaction mixture dropwise. Addition of water (40 ml) precipitated a yellow solid insoluble in methylene chloride. The latter was removed in vacuo and the yellowish green solid was collected in a Buchner funnel and washed with water. Yield: 2 g; m.p. 122°-125° C. Recrystallization from the minimum amount of boiling ethanol-benzene(1:1) afforded 1.6 g of product(58.6% crude yield).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([CH2:22][CH3:23])[C:10]([N:11]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH2:12][CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([CH3:34])[C:27]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.O>[CH:19]1([CH2:18][N:11]([C:10]2[C:9]([CH2:22][CH3:23])=[N:8][N:7]3[C:2]([C:27]4[C:28]([CH3:34])=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=4[O:25][CH3:24])=[CH:3][CH:4]=[CH:5][C:6]=23)[CH2:12][CH:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH2:21][CH2:20]1
Reactant: CCc1nn2c(Br)cccc2c1N(CC1CC1)CC1CCOC1
Reactant: COc1cc(C)c(OB(O)O)c(OC)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nn2c(-c3c(C)cc(OC)cc3OC)cccc2c1N(CC1CC1)CC1CCOC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
After dissolving N-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethyl-N-tetrahydro-3-furanylmethylamine (150 mg) in 1,2-dimethoxyethane (20 mL) and water (10 mL), 2,4-dimethoxy-6-methylphenylboric acid (155 mg), tetrakis(triphenylphosphine)palladium(0) complex (92 mg) and barium hydroxide octahydrate (250 mg) were added and the mixture was heated and stirred at 80° C. for 1 hour. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the organic layer washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the title compound (88 mg) was obtained from the n-hexane:ethyl acetate (6:1) fraction as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.ClC1C2N(C(CCC)=NN=2)[C:23]2[C:28]([N:29]=1)=[CH:27][CH:26]=[CH:25]C=2>>[CH2:15]([C:12]1[N:4]2[C:5]3[C:10]([N:11]=[C:2]([NH:29][CH:28]4[CH2:27][CH2:26][CH2:25][CH2:23]4)[C:3]2=[N:14][N:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCc1nnc2c(Cl)nc3ccccc3n12
Reactant: CCCc1nnc2c(Cl)nc3ccccc3n12
Product: CCCCc1nnc2c(NC3CCCC3)nc3ccccc3n12

Procedure:
The title compound was prepared essentially as described in Example 4 substituting 4-chloro-1-butyl[1,2,4]triazolo[4,3-a]quinoxaline for 4-chloro-1-propyl[1,2,4]triazolo[4,3-a]quinoxaline; mp 195°-197° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].CN(C1C=CC=CN=1)C.[NH2:21][C:22]1[C:39]([OH:40])=[CH:38][C:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30][C:24]=2[CH:23]=1>C(Cl)Cl>[OH:40][C:39]1[C:22]([NH:21][S:8]([CH3:7])(=[O:10])=[O:9])=[CH:23][C:24]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:27][CH2:26][C:25]=2[CH:38]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)cc2CC1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(O)c(NS(C)(=O)=O)cc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (0.17 ml), methanesulfonyl chloride (0.16 ml) and dimethylaminopyridine (catalytic quantity) were added at 0° C. to a solution in DCM (10 ml) of 1,1-dimethylethyl 7-amino-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (0.5 g). The solution was stirred at room temperature overnight. Volatiles were evaporated under reduced pressure and the residue was partitioned between aqueous NaHCO3 and DCM. The organic layer was concentrated and submitted to column chromatography to provide the title compound (0.53 g) as a yellow oil. MS (m/z): 357 [MH]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11]Cl)[S:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CN(C=O)C.C(Cl)Cl>[O:22]1[CH2:23][CH2:24][N:19]([CH2:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1csc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1csc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
2-Chloromethyl-thiazole-4-carboxylic acid ethyl ester (500 mg, 2.431 mmol) and potassium carbonate (504 mg, 3.65 mmol) were dissolved in dry DMF and morpholine (0.212 ml, 2.431 mmol) was added. The reaction mixture was stirred at RT overnight, diluted with DCM and washed with NaHCO3 and water. Organic phase was evaporated to dryness to yield the title compound (93%). 1H-NMR (400 MHz; DMSO-d6): δ 1.30 (t, 3H), 2.49-2.54 (m, 4H, overlap with DMSO), 3.58-3.63 (m, 4H), 3.84 (s, 2H), 4.29 (q, 2H), 8.47 (s, 1H). m/z [256.3+1].
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.Cl.[C:24]12([CH2:34][CH2:35][NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>O1CCCC1.C(OCC)(=O)C>[C:24]12([CH2:34][CH2:35][N:36]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:1]([NH:13][CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[O:2])[CH2:31][CH:30]3[CH2:29][CH:28]([CH2:27][CH:26]([CH2:32]3)[CH2:25]1)[CH2:33]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCCc1ccncc1
Reactant: CCCCCNCCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.6 %

Procedure:
1,1′-Carbonyldiimidazole (427 mg, 2.63 mmol) was added to a solution of 4-(3-aminopropyl)pyridine (Intermediate No. 2-1) (285 mg, 2.09 mmol) in tetrahydrofuran (10 ml), and the mixture was stirred at room temperature for 20 minutes. 2-(1-Adamantyl)-N-pentylethylamine hydrochloride (Intermediate No. 1-1) (571 mg, 2.00 mmol) was added to the mixture, and the whole was refluxed for one hour. The reaction mixture was diluted with ethyl acetate (50 ml), the whole was washed with a saturated aqueous sodium hydrogencarbonate solution (50 ml) and a saturated aqueous sodium chloride solution (50 ml) successively, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the precipitated solid was washed with diisopropyl ether and filtered off to give 606 mg (73%) of the titled compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].C(=O)([O-])[O-].[K+].[K+].[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1.CC(C)=O>CCCCCC>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O=C1CCc2ccc(OCCCCCl)cc2N1
Yield: 78 %

Procedure:
1-bromo-4-chloro-butane (3.4 g, 20 mmol), anhydrous potassium carbonate powder (4.14 g, 30 mmol) and 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (1.63 g, 10 mmol) are added to 10 ml of acetone and reflux for 24 hours. The reaction solution is evaporated to dryness and dispersed with 20 ml of dichloromethane and 20 ml of water respectively. The organic layer is extracted with water (20 ml×2) and saturated saline (20 ml) successively, dried over anhydrous magnesium sulfate, and evaporated to dryness to obtain a light yellow powder. The powder is slurried in n-hexane (20 ml×3), filtered, and dried to obtain 1.98 g of 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone, with a yield of 78%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][C:10]([OH:12])=O.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:33])[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30]>ClCCl.CO>[ClH:19].[Cl:19][C:20]1[CH:21]=[C:22]([NH:33][C:10](=[O:12])[C:9]#[C:8][C:7]2[CH:6]=[CH:5][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:3][C:2]=2[Br:1])[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30]
Reactant: CCN(CC)CCc1ccc(N)cc1Cl
Reactant: O=C(O)C#Cc1ccc(-c2ccccc2)cc1Br
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCc1ccc(NC(=O)C#Cc2ccc(-c3ccccc3)cc2Br)cc1Cl
Product: Cl

Procedure:
Prepared analogously to Example 2.3.f. from (3-bromobiphenyl-4-yl)propynoic acid and 3-chloro-4-(2-diethylaminoethyl)phenylamine. Yield: 95 mg (23.8% of theory); C27H26BrClN2O*HCl (M=546.32); calc.: molecular ion peak (M+H)+: 509/11/13; found: molecular ion peak (M+H)+: 509/11/13; Rf value: 0.3 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:12][CH2:13][NH:14][C:15](N1C=CN=C1)=[O:16])[CH3:2]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[C:15](=[O:16])[NH:14][CH2:13][CH2:12][C:4]=12)[CH3:2]
Reactant: CCc1c(CCNC(=O)n2ccnc2)[nH]c2ccccc12
Solvent: Cc1ccccc1
Product: CCc1c2n(c3ccccc13)C(=O)NCC2
Yield: 9 %

Procedure:
A solution of N-[2-(3-ethylindol-2-yl)ethyl]-1-imidazolecarboxamide (2.2 g) in toluene (50 ml) was refluxed for 3 hours. After the mixture was evaporated in vacuo, the residue was purified by silica gel column chromatography (5% methanol-chloroform) to give 5-ethyl-3,4-dihydropyrimido[1,6-a]indol-1(2H)-one (0.15 g).