Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[C:12]([C:15]1[N:16]=[C:17]([CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:18][C:19]=1[CH2:20][CH2:21][CH3:22])(O)=[O:13].Cl.[CH3:40][O:41][C:42](=[O:45])[CH2:43][NH2:44].Cl.C(C(NCCCN(C)C)=N)C.CN1CCOCC1>C(Cl)Cl.C1COCC1>[CH3:40][O:41][C:42](=[O:45])[CH2:43][NH:44][C:12]([C:15]1[N:16]=[C:17]([CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]2[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[NH:18][C:19]=1[CH2:20][CH2:21][CH3:22])=[O:13]
Reactant: COC(=O)CN
Reactant: CCCc1[nH]c(C2Cc3ccccc3N2C(=O)OC(C)(C)C)nc1C(=O)O
Agent: CCC(=N)NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: CCCc1[nH]c(C2Cc3ccccc3N2C(=O)OC(C)(C)C)nc1C(=O)NCC(=O)OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.2 %

Procedure:
1-Hydroxybenzotriazole hydrate (0.00158 mole) was added to a solution of compound 105 (0.00079 mole) in DCM (80 ml). Glycine methylester hydrochloride (0.00103 mole), N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3 propanediamine monohydrochloride (0.00103 mole) and 4-methylmorpholine (0.00103 mole) were added. THF (25 mm) was added. The reaction was stirred at room temperature for 3 days. The mixture was extracted with water. The organic phase was washed with saturated NaHCO3, 2N citric acid, saturated NaHCO3, dried over MgSO4, filtered, and concentrated, yielding 0.20 g of 1,1-dimethylethyl 2,3-dihydro-2-[4-[[(2-methoxy-2-oxoethyl)amino]carbonyl]-5-propyl-1H-imidazol-2-yl]-1H-indole-1-carboxylate (compound 109).
Reaction SMILES: [CH3:1][S:2]([CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH2:27][CH3:28])[NH:16][C:17](=[O:18])[C:11]2=[CH:10][N:9]=1)=[O:3].ClC1C=C(C=CC=1)C(OO)=[O:34]>ClCCl>[CH3:1][S:2]([CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH2:27][CH3:28])[NH:16][C:17](=[O:18])[C:11]2=[CH:10][N:9]=1)(=[O:34])=[O:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCOc1ccccc1-c1nc2nc(NCCCS(C)=O)ncc2c(=O)[nH]1
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(NCCCS(C)(=O)=O)ncc2c(=O)[nH]1

Procedure:
A solution of 7-(3-methylsulphinylpropylamino)-4-oxo-2-(2-propoxyphenyl)-3,4,-dihydropyrimido[4,5-d]pyrimidine (0.80 g) and m-chloroperoxybenzoic acid (0.40 g) in dichloromethane (50 ml) was stirred at ambient temperature for 24 hours. During this time further m-chloroperoxybenzoic acid (about 200 mg) was added on 2 occasions. The solution was washed with dilute aqueous sodium bicarbonate (3×25 ml) and the combined washings back-extracted with a little dichloromethane. The combined organic layer was washed with water and then brine, dried (magnesium sulphate) and evaporated under reduced pressure to yield a residue. This was recrystallized three times from methanol to yield the title compound, 0.51 g, m.p. 222-3° C.
Reaction SMILES: ClCCl.[CH2:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:5].C(O)(=O)C.[I:22]I>FC(F)(F)S([O-])(=O)=O.[Ag+].C(OCC)(=O)C>[CH2:4]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([I:22])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH3:5]
Reactant: II
Reactant: CCN1CCC(c2ccccc2)CC1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCN1CCC(c2ccc(I)cc2)CC1
Reaction time: 8 h

Procedure:
A dichloromethane (36 mL) mixture of 1-ethyl-4-phenylpiperidine (1.37 g, 7.23 mmol), acetic acid (500 μL), silver trifluoromethanesulfonate (3.72 g), and iodine (3.67 g) was stirred overnight. Ethyl acetate was added, then the insoluble matter was removed by filtration. The obtained filtrate was washed with ammonia water, aqueous sodium thiosulfate solution and saturated saline. After dried with anhydrous magnesium sulfate, this was concentrated and purified by flash column chromatography (FPNH, hexane:ethyl acetate=1 to 9:1) to obtain a mixture of the entitled compound and 1-ethyl-4-phenylpiperidine (2.52 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][C:21]([CH2:25][OH:26])([OH:24])[CH2:20][CH2:19]2)[CH:3]=1.[NH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O1CCOCC1.C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([N:18]3[CH2:23][CH2:22][C:21]([CH2:25][OH:26])([OH:24])[CH2:20][CH2:19]3)[CH:3]=[C:2]([NH:27][C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: Nc1cnccn1
Reactant: C[C@H](Nc1nc(Cl)cc(N2CCC(O)(CO)CC2)n1)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CCC(O)(CO)CC2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
100 mg of (S)-1-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}-4-(hydroxymethyl)piperidin-4-ol, 32 mg of 2-aminopyrazine, 45 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 38 mg of sodium t-butoxide and 27 mg of tris(dibenzylideneacetone)(chloroform)palladium were added in turn to a degassed mixed solution of 3 ml of toluene and 2 ml of 1,4-dioxane, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 80 mg of the objective compound as brown powder.
Reaction SMILES: [C:1]1([C@H:7]([NH:25][C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])[C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[O:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[CH2:41][CH2:40][O:39][CH:38]1[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][NH2:49])=[CH:44][CH:43]=1.C(OC(OCC)CCCN)C>>[N:31]12[CH2:32][CH2:33][CH:34]([CH2:35][CH2:36]1)[C@@H:29]([O:28][C:26](=[O:27])[NH:25][C@H:7]([C:8]1[CH:24]=[CH:23][CH:22]=[C:10]([O:11][CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:49][CH2:48][C:45]4[CH:44]=[CH:43][C:42]([CH:38]5[O:39][CH2:40][CH2:41][O:37]5)=[CH:47][CH:46]=4)=[CH:15][CH:14]=3)[CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:30]2
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Reactant: NCc1ccc(C2OCCO2)cc1
Agent: CCOC(CCCN)OCC
Product: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)NCc3ccc(C4OCCO4)cc3)cc2)c1)O[C@H]1CN2CCC1CC2

Procedure:
The title was prepared as described in Example 5 Step 1 with 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoic acid and (4-(1,3-dioxolan-2-yl)phenyl)methanamine replacing 1-methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-1H-pyrazole-3-carboxylic acid and 4-aminobutyraldehyde diethyl acetal respectively.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]([C:23](=O)C)[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:10][CH:11]=2)[C:6](=[C:26]([O:33][CH2:34][CH3:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]1=[O:36])(=[O:3])[CH3:2].CC(C)([O-])C.[K+].IC.O>CS(C)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]([CH3:23])[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:10][CH:11]=2)/[C:6](=[C:26](/[O:33][CH2:34][CH3:35])\[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)/[C:5]1=[O:36])(=[O:3])[CH3:2]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc(N(C(C)=O)S(=O)(=O)c3ccccc3)cc21)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CI
Product: CCO/C(=C1\C(=O)N(C(C)=O)c2ccc(N(C)S(=O)(=O)c3ccccc3)cc21)c1ccccc1

Procedure:
10 g (20 mmol) of 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-acetyl-N-phenylsulphonyl-amino)-2-indolinone (Example 1e) are dissolved in 150 ml of DMSO and combined with 2.2 g (20 mmol) of potassium tert. butoxide with stirring. After 15 minutes' stirring 1.9 ml (31 mmol) of iodomethane are added. The mixture is stirred for 3 hours at ambient temperature. Then another 2.2 g (20 mmol) of potassium tert. butoxide and 1 ml (16 mmol) of iodomethane are added. The mixture is stirred for 18 hours at ambient temperature. Then water is added. The reaction mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and evaporated to dryness. The residue is chromatographed on silica gel (petroleum ether/dichloromethane, 7:3).
Reaction SMILES: [Cl-].[NH4+].[NH2:3][C:4]1[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]>[Fe].C(O)C.O>[NH2:3][C:4]1[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: Nc1c(C(=O)OCc2ccccc2)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc(C(=O)OCc2ccccc2)c1N
Yield: 97.6 %

Procedure:
Iron powder (0.78 g) and ammonium chloride (0.15 g) were added in that order to an ethanol/water (4/1) solution (40 mL) of benzyl 2-amino-3-nitrobenzoate (0.38 g), and this was heated under reflux for 20 minutes with vigorous stirring. The insoluble matter was separated by filtration while hot, and the filtrate was evaporated under reduced pressure to about ⅕, and then aqueous sodium hydrogencarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried, and evaporated under reduced pressure to obtain benzyl 2,3-diaminobenzoate (0.33 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]#[N:8].C(OB(OC(C)C)OC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].Br[C:31]1[CH:45]=[CH:44][C:34]2[NH:35][C:36](=[O:43])[O:37][C:38]([CH2:41][CH3:42])([CH2:39][CH3:40])[C:33]=2[CH:32]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C1COCC1.O>[CH2:41]([C:38]1([CH2:39][CH3:40])[C:33]2[CH:32]=[C:31]([C:6]3[N:2]([CH3:1])[C:3]([C:7]#[N:8])=[CH:4][CH:5]=3)[CH:45]=[CH:44][C:34]=2[NH:35][C:36](=[O:43])[O:37]1)[CH3:42]
Reactant: CCC1(CC)OC(=O)Nc2ccc(Br)cc21
Reactant: Cn1cccc1C#N
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(CC)OC(=O)Nc2ccc(-c3ccc(C#N)n3C)cc21
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a solution of 1-methyl-1H-pyrrole-2-carbonitrile (4.1 g, 35 mmol) and triisopropylborate (8.9 mL, 38.5 mmol) in THF (80 mL) at 0° C. was added lithium diisopropylamide (22.8 mL, 45.5 mmol). The reaction mixture was allowed to warm to room temperature. Upon completion by TLC, the reaction was added dropwise to a 65° C. solution of 6-bromo-4,4-diethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (2.0 g, 7.0 mmol), potassium carbonate (2.9 g, 21 mmol) dissolved in (25 mL water), and tetrakistriphenylphosphine palladium (0) (0.4 g, 0.35 mmol) in tetrahydrofuran (20 mL). Upon completion by TLC of the reaction, it was poured into a saturated solution of ammonium chloride (200 mL), extracted with ethyl acetate (100 mL), dried with magnesium sulfate, and concentrated. Trituration of the residue with ethyl acetate/dichloromethane gave 5-(4,4-diethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile (1.2 g, 55%) as an off-white solid. 1H NMR (DMSO-d6): δ 10.26 (s, 1H), 7.37 (d, 1H, J=8.2, 1.6 Hz), 7.31 (d, 1H, J=1.8 Hz), 7.03 (d, 1H, J=4.0 Hz), 6.96 (d, 1H, J=8.2 Hz), 6.32 (d, 1H, J=4.0 Hz), 3.69 (s, 3H), 2.02 (m, 2H, J=7.3 Hz), 1.88 (m, 2H, J=7.3 Hz), 0.78 (t, 6H, J=7.3 Hz). MS (ESI) m/z 310 ([M+H]+); MS (ESI) m/z 308 ([M−H]−). HRMS: calcd for C18H19N3O2, 309.1477; found (ESI_FT), 310.15488;
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[S:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2)(=[O:14])=[O:13].N1C=CC=CC=1>ClCCl>[N:1]1([S:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18]3)(=[O:13])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1Cc2cc(S(=O)(=O)N3CCCc4ccccc43)ccc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoline (Aldrich), 5-chlorosulfonyl-2-oxindole and pyridine in dichloromethane was stirred at room temperature overnight. The reaction was concentrated and the residue recrystallized from methanol to vie 5-(3,4, -dihydro-2H-quinoline-1-sulfonyl)-1,3-dihydro-indol-2-one. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 10.74 (s, 1H, NH), 7.84–7.90 (d, 1H, SO2NH), 7.67–7.72 (m, 2H, 2×CH), 7.01–7.16 (m, 4H, aromatic), 6.95–6.97(d, 1H, CH), 4.28–4.29 (m, 1H), 3.58 (s, 2H, CH2), 2.59–2.65 (m, 2H), 1.75–1.77 (m, 2H), 1.53–1.61 (m, 2H). MS m/z 329 [M+1].
Reaction SMILES: CS[C:3]1[N:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:7]2[CH:6]=[CH:5][N:4]=1.[CH2:13]([N:20]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([N:20]1[CH:24]=[C:23]([C:3]2[N:8]3[N:9]=[C:10]([NH2:12])[N:11]=[C:7]3[CH:6]=[CH:5][N:4]=2)[CH:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cnn(Cc2ccccc2)c1
Reactant: CSc1nccc2nc(N)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nc2ccnc(-c3cnn(Cc4ccccc4)c3)n2n1
Temperature: 130 °C

Procedure:
A microwave vial containing 5-methylsulfanyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-ylamine (0.05 g, 0.276 mmol), 1-benzyl-1H-pyrazole-4-boronic acid (123 mg, 0.607 mmol), copper(1)thiophene carboxylate (116 mg, 0.607 mmol) and tetrakis(triphenylphosphine)palladium (33 mg, 0.028 mmol) in THF (1.2 mL) was heated under microwave irradiation (130° C., 15 min). The reaction mixture was filtered through celite and the cake washed with dichloromethane. The filtrate was washed with water followed by brine, dried over magnesium sulfate and concentrated under vacuum. Trituration with diethyl ether provided a yellow solid that did not require further purification. Yield: 0.05 g, 63%; LCMS method: 2, RT: 3.18 min, MI: 292 [M+1].
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:17].O>O1CCCC1>[CH3:17][O:15][C@H:12]1[CH2:13][CH2:14][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
Sodium hydride (2.2 g, 80% dispersion in mineral oil, 73.2 mmol) was added to an ice-cooled solution of (3S)-N-tert-butoxycarbonylpyrrolidin-3-ol (U.S. Pat. No. 6,180,627 preparation 78), (12.5 g, 66.7 mmol) in tetrahydrofuran (330 ml), and the solution was stirred at room temperature for an hour. Iodomethane (14.5 g, 100 mmol) was then added and the reaction stirred for 18 hours. Water (100 ml) was added and the mixture concentrated under reduced pressure to remove the organic solvents. The solution was partitioned between water (750 ml) and ethyl acetate (750 ml) the layers separated, and the organic solution dried over magnesium sulphate and evaporated under reduced pressure to give the title compound.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:18]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH2:17])=[C:16]([Br:18])[C:11]=3[N:10]=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)ncn2CC1CCCCC1
Reactant: BrBr
Agent: N
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc2c(ncn2CC2CCCCC2)c1Br
Yield: 40 %

Procedure:
To a solution of 1-cyclohexylmethyl-5-aminobenzimidazole (2.5 g, 11 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 1.37 g (4.3 mmol, 40%) of the product.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[C:15]([O:16][CH2:17][CH:18]4[CH2:20][CH2:19]4)=[CH:14][C:13]([CH:21]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:22]([O:24]CC4CC4)=[O:23])=[C:12]([F:33])[CH:11]=3)[CH:7]=[CH:6][C:5]=12>CCO.O.[OH-].[K+]>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[C:15]([O:16][CH2:17][CH:18]4[CH2:20][CH2:19]4)=[CH:14][C:13]([CH:21]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:22]([OH:24])=[O:23])=[C:12]([F:33])[CH:11]=3)[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(OCC2CC2)c(-c2ccc3nonc3c2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CC(C(=O)O)c1cc(OCC2CC2)c(-c2ccc3nonc3c2)cc1F

Procedure:
Cyclopropylmethyl 2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoate (0.14 g, 0.29 mmol) was dissolved in a mixture of EtOH/H2O (9 mL/1 mL) and KOH (0.3 g) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure to give a colorless oil. Purification by gradient column chromatography on silica gel Heptane-EtOAc (50:1-9:1) gave 2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoic acid as a white solid (0.12 g, quantitative); pure portion (0.03 g, 25%); white microcrystals, M.P.=110-111° C., 1H NMR (300 MHz, CDCl3/TMS): δ 8.99 (br s, 1H), 7.66 (br s, 4H), 7.05 (d, J=9.9 Hz, 1H), 6.94 (d, J=5.2 Hz, 1H), 4.08 (t, J=7.7 Hz, 1H), 3.76 (d, J=6.6 Hz, 2H), 2.04-1.90 (m, 1H), 1.81-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.32-1.05 (m, 2H), 0.94 (d, J=6.0 Hz, 6H), 0.54 (d, J=7.4 Hz, 2H), 0.24 (d, J=3.9 Hz, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.2, 154.7 (d, 1JCF=239.8 Hz), 152.0, 140.6, 132.0, 129.9, 129.6, 125.7 (d, 2JCF=16.2 Hz), 124.8 (q, 3JCF=3.6 Hz), 124.0 (q, 1JCF=270 Hz), 117.2 (d, 2JCF=25.2 Hz), 113.9, 74.2, 41.3, 29.8, 25.9, 22.8, 22.1, 10.3, 3.2.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[NH2:9][CH2:10][CH2:11][NH2:12].Cl>CO.O>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][NH:9][CH2:10][CH2:11][NH2:12])=[CH:4][CH:5]=1
Reactant: C=Cc1ccncc1
Reactant: NCCN
Agent: Cl
Solvent: CO
Solvent: O
Product: NCCNCCc1ccncc1

Procedure:
A solution of 4-vinylpyridine (52.5 g) in methanol (250 cm3) was added dropwise over 2 hours to a stirred solution of 1,2-diaminoethane in methanol (500 cm3) and water (500 cm3) under reflux in the presence of an excess of concentrated hydrochloric acid (pH1). After a further 1.5 hours the mixture was concentrated in vacuo and basified to pH9 with 4M sodium hydroxide solution. The solution was extracted with chloroform (4×150 cm3) and the dried (MgSO4) extracts were evaporated in vacuo to give an oil. Distillation gave N-[2-(4-pyridyl)ethyl]-1,2-diaminoethane as a colourless oil, b.p. 119°-122°/0.09 mm (27.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[C:13]1([S:19]([CH2:21][CH2:22][CH2:23][CH2:24]Br)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][C:6](=[O:12])[NH:7]3)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: O=S(CCCCBr)c1ccccc1
Product: O=C1CCc2c(cccc2OCCCCS(=O)c2ccccc2)N1

Procedure:
Prepared analogous to Example 4 from 5-hydroxy-3,4-dihydro-carbostyril and 4-phenylsulfinyl-butyl bromide.
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:22][C:23]1([CH3:31])[CH2:30][C:28](=O)[CH2:27][C:25](=[O:26])[CH2:24]1.C1(C)C=CC=CC=1>O>[NH2:17][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=2)[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:28]3[CH2:30][C:23]([CH3:31])([CH3:22])[CH2:24][C:25](=[O:26])[CH:27]=3)[CH2:3][CH2:2]2)[N:16]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2nc(N3CCN(C4=CC(=O)CC(C)(C)C4)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 2.9 g (0.01 mol) of 2-piperazino-4-amino-6,7-dimethoxyquinazoline, 1.4 g (0.01 mol) of dimedone and 20 ml of toluene is heated at the boiling point under reflux for 4 hours, using a water separator. After cooling the solution, the reaction product precipitates. It is washed with petroleum ether and recrystallised from 220 ml of acetonitrile. 2.6 g of melting point 185°-187° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38]([N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][NH:44][CH3:45])=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7].[CH:56]([C:58]1[S:62][C:61]([C:63]([OH:65])=O)=[CH:60][CH:59]=1)=[O:57].Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:53][C:50]([F:51])([F:52])[C:48]1[CH:47]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:55])[F:54])[CH:49]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38]([N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][N:44]([CH3:45])[C:63]([C:61]3[S:62][C:58]([CH:56]=[O:57])=[CH:59][CH:60]=3)=[O:65])=[O:39])[CH2:26][CH2:27]2)([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[O:10][CH2:9]1)=[O:7]
Reactant: CNCCCN(C)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Reactant: O=Cc1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CN(CCCN(C)C(=O)c1ccc(C=O)s1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
The compound (73 mg, 0.157 mmol) obtained in Example 1k was dissolved in methylene chloride (3 mL), 5-formyl-thiophene-2-carboxylic acid (40 mg, 0.257 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (89 mg, 0.464 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogencarbonate solution was added, and then the mixture was extracted with ethyl acetate (×3) and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=40:1→20:1, v/v) to give the title compound (144 mg; yield, 61%) as a white solid.