Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]([C:13](=[O:28])[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[OH-].[K+].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>O.CN(C)C=O>[CH3:31][S:32]([C:2]1[CH:3]=[CH:4][C:5]([C:13](=[O:28])[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)(=[O:34])=[O:33]
Reactant: O=C1CCc2c(C(=O)CCN3CCN(c4ccccc4)CC3)ccc(O)c2N1
Reactant: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)CCN2CCN(c3ccccc3)CC2)c2c1NC(=O)CC2

Procedure:
37.9 Grams of 8-hydroxy-5-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyril and 5.9 g of potassium hydroxide were dissolved in 400 ml of water and the solution was concentraed under a reduced pressure to obtain a residue. The residue was dissolved in 400 ml of dimethylformamide and the 12.0 g of methane-sulfonyl chloride was added dropwise to the solution under cooling condition. One hour after the addition either was added to the reaction mixture to obtain crystals. The crystals were collected by filtration and washed with acetone, then recrystallized from isopropanol to obtain 35.9 g of 8-methanesulfonyl-5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyril in light brown needle-like crystals. Melting point: 165°-167° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[S:21][C:20]2[C:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1>>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:19]3[C:20]4[S:21][C:13]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[CH:14][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:24][CH:25]=2)=[CH:31][CH:32]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1ccc(Nc2ccc(Nc3ncnc4cc(Br)sc34)cc2)cc1
Product: COc1ccc(Nc2ccc(Nc3ncnc4cc(-c5ccc(OC)cc5)sc34)cc2)cc1

Procedure:
The title compound was prepared from 2-methoxybenzeneboronic acid and N-(6-bromo-thieno[3,2-d]pyrimidin-4-yl)-N′-(4-methoxy-phenyl)-benzene-1,4-diamine by a procedure analogous to example 2. M.P. 159-169° C.; LC-MS: 454.31 (MH+); HPLC RT: 7.003 minutes.
Reaction SMILES: C([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:23])[CH:13]([CH2:18][S:19][C:20](=[O:22])[CH3:21])[NH:14][C:15](=[O:17])[CH3:16])(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:15]([NH:14][CH:13]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:24])=[O:5])=[O:23])[CH2:18][S:19][C:20](=[O:22])[CH3:21])(=[O:17])[CH3:16]
Reactant: CC(=O)NC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
N,S-Diacetyl-DL-cysteinyl-L-proline tert-butyl ester (1.9 g) is dissolved in a mixture of anisole (6 ml) and trifluoroacetic acid (12 ml) and the solution is stored at room temperature for one hour. The solvents are removed in vacuo and the residue is precipitated from ethyl acetate-ether-hexane, to obtain N,S-diacetyl-DL-cysteinyl-L-proline, yield 1.08 g, m.p. 80°-140°.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+].O>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>[CH2:26]([O:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[CH:14][CH:15]=2)=[CH:24][CH:23]=1)[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C=O)cc3)cc2)cc1
Yield: 58 %

Procedure:
Under an argon atmosphere, (4-formylphenyl)boronic acid (0.54 g, 3.6 mmol), 4-Bromo-4′-pentyloxy-biphenyl (0.958 g, 3 mmol) 1) (A1), sodium hydrogen carbonate (0.76 g, 9 mmol), and tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (0.057 g, 0.030 mmol) were dissolved in THF (15 mL) and water (15 mL) and stirred under a reflux condition. After they reacted with each other, liquid separation and extraction were performed with water and chloroform. After an organic layer was dried with anhydrous sodium sulfate and filtered, the solvent was distilled off under a reduced pressure. After the obtained reaction mixture was separated and purified with a silica gel column chromatography using chloroform as a moving bed, the mixture was purified by a recrystallization method using chloroform and hexane. Thereby, a white solid of 4″-(pentyloxy)-[1,1′:4′,1″-terphenyl]-4-carbaldehyde (A2) was obtained (0.60 g, yield: 58%). The obtained product (A2) was identified by using a 1H-NMR method. 1H-NMR (CDCl3, 400 MHz) δ=10.06 (s, 1H, CHO), 7.95-7.97 (d, 2H, phenylene), 7.79-7.81 (d, 2H, phenylene), 7.71-7.66 (m, 4H, phenylene), 7.00-6.98 (s, 2H, phenylene), 4.03-3.99 (t, 2H, —O—CH2—), 1.84-1.81 (t, 2H, —CH2—), 1.47-1.40 (m, 4H, —CH2—), and 0.93-0.97 (t, 3H, —CH3). 13C NMR (CDCl3, 100 MHz) δ=191.7, 159.0, 146.7, 141.0, 137.8, 135.2, 132.4, 130.2, 128.0, 127.2, 114.9, 68.1, 29.0, 28.3, 22.7, and 14.1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]([CH3:20])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:22].O>O1CCOCC1.[Cu-]=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]([CH3:20])[CH:10]=[N:9][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:22])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: [NH4+]
Reactant: Cn1cnc(-c2ccnc(Br)c2)c1-c1ccc(F)cc1
Agent: O=[Cu-]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cnc(-c2ccnc(N)c2)c1-c1ccc(F)cc1

Procedure:
The crude 2-Bromo-4-[5-(4-fluoro-phenyl)-1-methyl-1H-imidazol-4-yl]-pyridine (196 mg), 28% aqueous ammonium hydroxide solution (2.0 mL) and copper (I) oxide (84 mg, 0.59 mmol) are mixed in 1,4-dioxane (3.0 mL) in a microwave reaction tube. The mixture is heated at 150° C. for 25 min in a microwave reactor before water (30 mL) is added. The resulting mixture is extracted with EtOAc (3×25 ml). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 72 mg of desired product.
Reaction SMILES: CS[C:3]([C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[F:32])=[N:4][C:5]([C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[C:10]([Br:13])[C:11]=1[CH3:12])=O.C(O)(=O)C(O)=O.[CH2:39]([NH:41][NH2:42])[CH3:40]>C1(C)C=CC=CC=1.CCOCC>[Cl:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([F:32])[C:25]=1[C:3]1[N:4]=[C:5]([C:7]2[S:8][C:9]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:18][CH:19]=3)=[C:10]([Br:13])[C:11]=2[CH3:12])[N:41]([CH2:39][CH3:40])[N:42]=1
Reactant: CCNN
Reactant: CSC(=NC(=O)c1sc(-c2ccc(OC(F)(F)F)cc2)c(Br)c1C)c1c(F)cccc1Cl
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCn1nc(-c2c(F)cccc2Cl)nc1-c1sc(-c2ccc(OC(F)(F)F)cc2)c(Br)c1C
Temperature: 25 °C
Reaction time: 64 h
Yield: 0 %

Procedure:
Methyl-N-{[3-methyl-4-bromo-5-(4-trifluoromethoxyphenyl)-2-thienyl]-carbonyl}-2-fluoro-6-chlorobenzenecarbimidothioate (0.85 g, 1.5 mmol) and ethylhydrazine oxalate (0.90 g, 6 mmol) were combined in toluene (5 mL) and stirred 64 h at 25° C. and heated to reflux for 18 h. The reaction mixture was diluted with ether and washed with 0.1 M hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated to a crude pale yellow oil. Chromatography (silica gel, 10% ethylacetate/hexane) afforded the product as a clear oil (0.250 mg, 30%): 1H NMR (CDCl3) δ 7.73 (2H, d), 7.0–7.5 (5H, m), 4.3 (2H, q), 2.40 (3H, s), 1.55 (3H, t); EI/MS 546 m/e (M+).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.S=C1N([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29](=[O:31])[CH3:30])=[C:24]([O:32][CH3:33])[CH:23]=2)=[O:19])CCS1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18](=[O:19])[NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)=[CH:23][C:24]=1[O:32][CH3:33])(=[O:31])[CH3:30]
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(COC(=O)NC2Cc3ccccc3C2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
2-Aminoindane hydrochloride (166 mg, 1.1×0.891 mmol) was suspended in solution of VII (304.2 mg, 0.891 mmol) in anhydrous THF (10 mL), triethylamine (198 mg, 275 μL, 2.2×0.891 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with CH2Cl2 and washed with 1N HCl, distilled water, and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate (1:1, v/v) to afford 134 mg (42%) white solid, 14: mp=114-116° C. (uncorrected); Rf=0.45 (hexanes/ethyl acetate, 1:1, v/v); 1HNMR (CDCl3) δ 7.20 (bs, 2H), 7.15 (m, 2H), 6.98 (d, 3J=8.0 Hz, 1H), 6.93 (d, 1H), 6.90 (dd, 3J=8.0 Hz, 1H), 5.04 (s, 2H, CH2O), 4.51 (bs, 2H), 3.81 (s, 3H, OCH3), 3.28 (dd, 3J=16 Hz, 4J=7.1 Hz, 2H), 2.80 (dd, 3J=16 Hz, 4J=4.5 Hz, 2H, NCH2), and 2.29 (s, 3H). Exact mass (ESI) calculated for C20H22NO5 [M+H]=356.1492. found 356.1496.
Reaction SMILES: [I-].C[N+]1C=CN([C:8](=[O:30])/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[O:22][C:17]=3[CH:16]=2)C=1.C(N(CC)C(C)C)(C)C.[NH:40]1[CH2:44][CH2:43][CH2:42][CH:41]1[C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>C(#N)C>[CH3:29][C:12]1[S:11]/[C:10](=[N:9]\[C:8]([N:40]2[CH2:44][CH2:43][CH2:42][CH:41]2[C:45]2[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=2)=[O:30])/[N:14]([C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:25])([F:26])[C:21]([F:23])([F:24])[O:22][C:17]=3[CH:16]=2)[CH:13]=1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: c1cncc(C2CCCN2)c1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)N2CCCC2c2cccnc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (Z)-3-methyl-1-(5-methyl-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2(3H)-ylidenecarbamoyl)-1H-imidazol-3-ium iodide core (Example 81A, 0.88 mL of 0.16 M in acetonitrile, 80 mg, 0.1 mmol) was added to a 20 mL vial, followed by N,N-diisopropylethylamine (0.88 mL of 0.2 M in acetonitrile, 24 mg, 0.13 mmol). 3-(Pyrrolidin-2-yl)pyridine (0.79 mL of 0.2 M in acetonitrile, 0.11 mmol) was added last. The resulting mixture was shaken at room temperature overnight. It was then concentrated in vacuo, and the residue was taken up in 1:1 MeOH/DMSO and purified by reverse phase HPLC (acetonitrile/water 0.1% TFA gradient elution method) to give the titled compound. 1H NMR (300 MHz, DMSO-d6/D2O) δ ppm 1.74-1.93 (3H) 2.12-2.21 (3H) 2.33-2.44 (1H) 3.50-3.68 (2H) 4.95-5.07 (1H) 6.91-7.06 (1H) 7.21-7.59 (3H) 7.70-7.91 (1H) 8.33-8.42 (1H) 8.44-8.52 (1H); MS (ESI+) m/z 495 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[F:14][C:15]([F:23])([F:24])[C:16]1[CH:17]=[C:18]([NH:19][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[OH:4])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1O

Procedure:
This compound was obtained as a white solid starting from acetylsalicyclic acid and 3trifluoromethylaniline using the same procedure described in example 5.
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:20][C:21](O)=[O:22])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].B(F)(F)F.CCOCC>>[OH:4][C:3]1[C:2]([CH3:1])=[C:8]([OH:9])[CH:7]=[CH:6][C:5]=1[C:21](=[O:22])[CH2:20][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=1
Reactant: Cc1c(O)cccc1O
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: FB(F)F
Solvent: CCOCC
Product: COc1ccc(CC(=O)c2ccc(O)c(C)c2O)cc1OC
Temperature: 110 °C

Procedure:
2-Methylresorcinol (6.285 g, 1 equivalent) and 3,4-dimethoxyphenylacetic acid (9.251 g, 1 equivalent) were added to a round bottom flask. The round bottom flask was attached to a condenser and placed in an oil bath, the whole system was kept under nitrogen. Distilled boron trifluoride diethyl etherate, BF3.OEt2 (42 ml, 5 equiv.) was added to the mixture while stirring. The mixture was refluxed (110° C.). A yellow solid formed at 75 minutes indicating that the reaction had gone to completion. The reaction was heated for a further 10 minutes and cooled to room temperature. The yellow solid was collected by suction filtration and washed with distilled water (200 ml) to remove any excess BF3.OEt2 present. 1H NMR in d-DMSO indicated the yellow solid was 1-(2,4-dihydroxy-3-methyl-phenyl)-2-(3,4-dimethoxy-phenyl)ethanone in >95% purity. The solid was dried on a freeze dryer for 24 hours (6.303 g, 43%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl[CH2:17][C@H:18]([N:25]1[C:34](=[O:35])[CH2:33][C:28]2([CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:27][C:26]1=[O:36])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C@@H:18]([N:25]2[C:34](=[O:35])[CH2:33][C:28]3([CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:27][C:26]2=[O:36])[CH2:17][N:13]2[CH2:12][CH2:11][N:10]([C:3]3[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH2:15][CH2:14]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Fc1cc(F)c(N2CCNCC2)cc1F
Reactant: O=C1CC2(CCCC2)CC(=O)N1[C@@H](CCl)c1ccccc1
Product: O=C1CC2(CCCC2)CC(=O)N1[C@@H](CN1CCN(c2cc(F)c(F)cc2F)CC1)c1ccccc1
Temperature: 160 °C
Reaction time: 5 h
Yield: 30.3 %

Procedure:
A mixture of 1-(2,4,5-trifluorophenyl)piperazine (20 mg, 0.093 mmol) and (R)-8-(2-chloro-1-phenylethyl)-8-azaspiro[4.5]decane-7,9-dione (20 mg, 0.066 mmol) was heated with stirring at 160° C. for 5 hours. The residue was purified by preparative TLC, giving the title compound as an off-white solid (9.5 mg, 0.020 mmol, 30%): ESI-MS m/z 486 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)[CH3:2].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:13](=[O:15])[CH2:12][CH2:11]1)[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOc1ccccc1C1CCC(=O)N1
Product: CCOc1ccccc1C1CCC(=O)N1Cc1ccc(F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2-ethoxyphenyl)pyrrolidin-2-one with commercially available 1-(bromomethyl)-4-fluorobenzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.01 min.; [M+H]+: 313.99 g/mol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([Br:12])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Br[CH2:14][C:15]([NH:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26])=[O:16].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.CO>C1(C)C=CC=CC=1.CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:14][C:15](=[O:16])[NH:17][C:18]2[C:19]([CH3:26])=[CH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])[C:8]([Br:12])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(Br)nc1C
Reactant: Cc1cc(C)c(NC(=O)CBr)c(C)c1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)c1c(C)nc(Br)n1CC(=O)Nc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-bromo-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester (1.00 g, 4.291 mmol) and 2-bromo-N-(2,4,6-trimethyl-phenyl)-acetamide (1.209 g, 4.720 mmol) in a mixture of toluene (16 mL) and acetone (8 mL) was added diazabicycloundecene (0.71 mL, 4.720 mmol). The resulting solution was stirred at room temperature for 24 h. Methanol (10 mL) was added to dissolve the precipitate formed, followed by the addition of silica gel (25 g). The solvent was removed under reduced pressure to dryness and the residue was applied to a silica gel-packed column. The isolation of the product was achieved by column chromatography (hexanes—ethyl acetate 4:1 to 1:2). Yield—0.736 g (42%). 1H NMR (DMSO d-6, 500 MHz) δ 9.52 (s, 1H), 6.86 (s, 2H), 5.15 (br s, 2H), 4.25 (q, J=7.1 Hz, 2H), 2.38 (s, 3H), 2.21 (s, 3H), 2.11 (s, 6H), 1.30 (t, J=7.1 Hz, 3H); LC/MS: tR=1.46 min., MS: [M+H]=408.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4]3[N:5]([C:13]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=4)=[N:14][CH:15]=2)[CH2:6][CH2:7][C:8]=3[NH:9][C:10](=[O:12])[CH:11]=1.[CH3:24][NH:25][CH3:26]>>[F:1][C:2]1[C:3]2[C:4]3[N:5]([C:13]([C:16]4[CH:23]=[CH:22][C:19]([CH2:20][N:25]([CH3:26])[CH3:24])=[CH:18][CH:17]=4)=[N:14][CH:15]=2)[CH2:6][CH2:7][C:8]=3[NH:9][C:10](=[O:12])[CH:11]=1
Reactant: O=Cc1ccc(C2=NC=C3C(F)=CC(=O)NC4=C3N2CC4)cc1
Reactant: CNC
Product: CN(C)Cc1ccc(C2=NC=C3C(F)=CC(=O)NC4=C3N2CC4)cc1

Procedure:
The title compound was prepared following the procedure described in Example 32 from aldehyde 97a and dimethylamine (2M/MeOH) to give 0.10 g (60%) of a white solid: mp=240° C. (dec); Rf=0.08 (7% methanolic ammonia/CHCl3); IR (KBr) 1669, 1607, 1487, 1458 cm−1; 1H NMR (DMSO-d6) δ 2.20 (s, 6H), 3.51 (s, 2H), 3.54-3.55 (m, 2H), 4.45-4.47 (m, 2H), 7.50 (d, 2H, J=8.2 Hz), 7.57-7.61 (m, 1H), 7.73-7.76 (m, 1H), 7.82 (d, 2H, J=8.2 Hz), 8.59-8.63 (m, 1H). HRMS calcd for C19H19N4OF 338.1543 (M+), found 338.1558. Anal. (C19H19N4OF0.2H2O) C, H, N. found 412.2124. Anal. (C25H25N5O.0.5 H2O, 3.5 TFA) C, H, N.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[C:31]([O:39][CH2:40][CH3:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1>CCOCC>[Br-:1].[CH2:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N+:34]1[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([O:39][CH2:40][CH3:41])=[O:38])[CH:33]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCOCCCOCCCCCCBr
Reactant: CCOC(=O)c1cccnc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCOCCCOCCCCCC[n+]1cccc(C(=O)OCC)c1
Product: [Br-]

Procedure:
1-Bromo-6-[3-(octadecyloxy)propoxy]hexane obtained in Reference Example 4 (1.0 g) is heated with ethyl nicotinate (0.66 g) at 90° C. for 19 hours. After the reaction mixture is cooled, ether is added to the reaction mixture and the precipitate is collected by filtration to give 1-N-[6-[3-(octadecyloxy)propoxy]-hexyl]-3-ethoxycarbonylpyridinium bromide (1.0 g). To this compound in methanol (25 ml) is added with stirring 2N sodium hydroxide (4 ml), and the mixture is stirred at room temperature for 20 minutes. The reaction mixture is neutralized with 1 N hydrochloric acid, concentrated under reduced pressure, and extracted with dichloromethane. The extract is washed with an aqueous solution saturated with sodium chloride, dried and concentrated. The residue is subjected to purification by means of silica gel chromatography (chloroform-methanol-water= 65:25:4) and then to reprecipitation from chloroform-acetone to give the above-titled compound as pale yellow powder (0.63 g).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[C:16](I)=[CH:15][C:14]([S:18][CH3:19])=[CH:13][N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1)#[CH:21].O>C(N(CC)CC)C>[C:1]1([S:7]([N:10]2[C:11]3=[N:12][CH:13]=[C:14]([S:18][CH3:19])[CH:15]=[C:16]3[CH:21]=[C:20]2[C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Reactant: C#Cc1ncccn1
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1cnc2c(c1)cc(-c1ncccn1)n2S(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A suspension of 2-benzenesulfonylamino-5-methylthio-3-iodo-pyridine (1.53 g), 2-ethynylpyrimidine (768 mg), bistriphenylphosphine palladium dichloride (259 mg) and cuprous iodide (70.3 mg) in triethylamine (37 ml) was stirred in a sealed tube at 100° C. for 1.5 hours. After cooling, the reaction solution was poured into water, extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 1.21 g of the desired product as a white crystal.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[CH2:9]([NH:11][CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([OH:18])[C:14]([F:17])([F:16])[F:15])[CH3:10]>>[CH2:9]([N:11]([CH2:12][C:13]([OH:18])([CH2:19][NH:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:14]([F:17])([F:16])[F:15])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:10]
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1cccs1
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 1 from 2-thiophenecarboxylic acid and 3-(Ethylamino)-1,1,1-trifluoro-2-{[(1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.
Reaction SMILES: [CH2:1]([C:4]1[C:13](OCC=C)=CC=C2[C:5]=1CCC(=O)N2)[CH:2]=C.[CH2:19]([C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][C:28](=[O:32])[NH:29]2)=[CH:24][C:23]=1[O:33][CH2:34][CH:35]=[CH2:36])[CH:20]=[CH2:21].[H-].[Na+].[H][H].C(Br)C=C(C)C>CN(C)C=O.O>[CH2:19]([C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][C:28](=[O:32])[N:29]2[CH2:2][CH:1]=[C:4]([CH3:13])[CH3:5])=[CH:24][C:23]=1[O:33][CH2:34][CH:35]=[CH2:36])[CH:20]=[CH2:21]
Reactant: C=CCOc1cc2c(cc1CC=C)NC(=O)CC2
Reactant: [H][H]
Reactant: C=CCOc1ccc2c(c1CC=C)CCC(=O)N2
Agent: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc2c(cc1CC=C)N(CC=C(C)C)C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
10.2 Grams of the mixture of 5-allyl-6-allyloxy-3,4-dihydro-2(1H)-quinolinone and 7-allyl-6-allyloxy-3,4-dihydro-2(1H)-quinolinone obtained in Example 16 was dissolved in 100 ml of dimethylformamide, then 2.2 g of 60% oily sodium hydride was added little by little, and stirred at 25° to 40° C. until generation of hydrogen gas was ceased. After the reaction mixture was cooled to room temperature, 9.1 g of prenyl bromide was added and stirred at room temperature for 8 hours. After the reaction was finished, water was added and extracted with methylene chloride, then the extract was washed with water and an aqueous solution saturated with sodium chloride in this order, and dried with anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated. Thus obtained residual oily product was subjected to separation and purification by means of a silica gel flush column chromatography, there was obtained 10.2 g (59.7%) of 7-allyl-6-allyloxy-3,4-dihydro-1-prenyl-2(1H)-quinolinone.