Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24](Cl)(=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:24](=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CC(C)CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)CC(C)C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with isovaleryl chloride (7.8 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenylamine (3.37 g, 9.24 mmol) in pyridine (30 ml) at 0° C. was charged with methanesulfonylchloride 1.3 ml, 16.5 mmol) dropwise, causing a color change from yellow to bright orange. The reaction was warmed to room temperature and judged complete by TLC after 3 h. The mixture was diluted with toluene and stripped twice. Following a water quench (20 ml), the product was extracted with EtOAc (4×30 ml), washed with saturated aqueous NaHCO3 solution (6×30 ml) and with saturated aqueous NaCl solution (3×30 ml), dried over Na2SO4, filtered and concentrated to a crude orange liquid. Flash chromatography on silica gel eluting with 2 to 5% MeOH/CH2Cl2 provided the title compound as orange oil (3.59 g, 85%). (TLC 5% MeOH/CH2Cl2 Rf 0.24); 1H NMR (400 MHz, CDCl3) δ 7.37-7.19 (m, 7H), 7.11 (br d, J=7.9 Hz, 1H), 7.05 (ddd, J=7.9, 2.1, 0.8 Hz, 1H), 3.73 (AB q, ΔAB 59.9, J=13.3 Hz, 2H), 3.71 (m, 1H), 3.09 (br, s, 1H), 3.04 (m, 1H), 2.94 (s, 3H), 2.80 (m, 1H), 2.18 (m, 2H), 2.07-1.95 (m, 4H), 1.82 (br d, J=12.0 Hz, 1H), 1.72 (m, 1H), 1.57 (m, 1H), 1.17 (m, 1H). 13C 154.2, 137.1, 132.3, 129.5, 129.4, 129.1, 128.6, 128.4, 127.1, 122.0, 118.3, 117.9, 60.1, 52.3, 49.4, 39.3, 38.9, 38.7, 37.4, 35.8, 24.9, 23.0; APCl MS m/z 385.1 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4([C:31]#[N:32])[CH2:30][CH2:29]4)[CH:23]=3)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[N:5]=2.Cl.Cl.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44](O)=[O:45])[CH2:39][CH2:38]1.Cl.C(N=C=NCCCN(C)C)C.CO>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:31]([C:28]1([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:6]3[N:5]=[C:4]4[S:3][C:2]([NH:1][C:44](=[O:45])[CH2:43][N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)=[N:10][C:9]4=[CH:8][CH:7]=3)[CH:13]=2)=[O:33])[CH2:30][CH2:29]1)#[N:32]
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2n1
Reactant: CN1CCN(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)CN3CCN(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (457 mg, 998 μmol) produced in Example C1(vii) in pyridine (10 mL) were added (4-methylpiperazin-1-yl)acetic acid dihydrochloride (474 mg, 2.05 mmol), N,N-dimethylpyridine-4-amine (51.3 mg, 420 μmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (403 mg, 2.10 mmol), and the mixture was stirred at room temperature for 2 hr. Methanol (10 mL) was added to the reaction solution, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and tetrahydrofuran (10 mL), and the solution was washed with 0.1N hydrochloric acid (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL). The earlier 0.1N hydrochloric acid washing solution was neutralized (pH 7.0) with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate (50 mL×2). The combined organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give the title compound (419 mg, 70%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][NH:14][CH3:15].[CH2:16]=O.Cl>C(O)(C)C>[Cl:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH2:8][CH2:13][N:14]([CH3:16])[CH3:15])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CNC
Reactant: C=O
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: Cl
Solvent: CC(C)O
Product: CN(C)CCC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a solution of 1-(5-chloro-4-nitro-2-thienyl)ethanone (1 g, 4.9 mmol) in isopropanol (20 mL), was added dimethylamine (0.55 g, 6.8 mmol) and paraformaldehyde (0.22 g, 7.3 mmol) and concentrated hydrochloric acid (0.2 mL). The resulting reaction mixture was heated at 80° C. for 18 hours. After this time, the reaction mixture was cooled to 0° C. and stirred at 0° C. for 1 hour. A pale yellow precipitate formed and collected by filtration to afford the corresponding hydrochloride salt of the title product (0.55 g, 38% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.39 (1H, m), 8.69 (1H, s), 3.68 (2H, m), 3.38 (2H, m), 2.80 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]([C:13]([OH:15])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[ClH:19].[CH3:1][O:2][C:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]([C:13]([Cl:19])=[O:15])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C(=O)O)c2cccnc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)c2cccnc12
Product: Cl
Reaction time: 24 h

Procedure:
A suspension of 8-methoxyquinoline-5-carboxylic acid (5.0 g) in dichloromethane (50 ml) was cooled to 20 C. Oxalyl chloride (4.29 ml) was added cautiously and then dry dimethylformamide (8 drops) was added dropwise. The mixture was stirred at 0° C. for 1h and then at room temperature for 24h. The solvent was removed in vacuo and the residue azeotroped with a small amount of toluene. The title compound was obtained as a brown solid (5.18 g).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:24])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:27][N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]1[N:37]2[CH:38]=[C:39]([O:42][C@@H:43]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[C@@H:45]([NH2:52])[CH2:44]3)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:52][C@@H:45]2[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:43]([O:42][C:39]3[CH:40]=[CH:41][C:36]4[N:37]([C:33]([C@@H:29]5[CH2:30][CH2:31][CH2:32][N:28]5[CH3:27])=[N:34][N:35]=4)[CH:38]=3)[CH2:44]2)=[O:24])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[N:9]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@H]3C[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(CO)cc2)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@H]3C[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CO)cc4)c4ccccc43)cn12

Procedure:
A solution of Intermediate 33a (190 mg, 0.454 mmol), Intermediate 37a (132 mg, 0.378 mmol) and DIPEA (132 μL, 0.756 mmol) in anhydrous DMF (3 mL) was stirred at 100° C. for 3 h. After cooling, the mixture was partitioned between EtOAc (50 mL) and water (50 mL), and then extracted into EtOAc (3×50 mL). The combined organics were washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as give an off-white solid after freeze-drying (143 mg, 61%). LCMS (Method 5): Rt 3.23, m/z 621 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.22 (9H, s), 1.95-1.97 (3H, m), 2.07 (3H, s), 2.20-2.23 (3H, m), 2.52-2.53 (1H, m), 3.10 (1H, m), 3.92 (1H, t, J 8.1), 4.51 (2H, d, J 5.6), 5.25-5.27 (2H, m), 5.83 (1H, d, J 5.8), 6.25 (1H, s), 6.99 (1H, d, J 7.9), 7.18 (1H, dd, J 9.9, 2.2), 7.24-7.32 (2H, m), 7.35-7.41 (6H, m), 7.67 (1H, d, J 9.9), 8.10 (1H, s), 8.20 (1H, s).
Reaction SMILES: Cl.Cl.[N:3]1([C:10]2[CH:11]=[C:12]([CH2:20][CH3:21])[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[CH2:23][C:24]1[N:25]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:27][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH2:20]([C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([N:3]3[CH2:9][CH2:8][CH2:7][N:6]([CH2:23][C:24]4[N:25]=[C:26]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[S:27][CH:28]=4)[CH2:5][CH2:4]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)[CH3:21]
Reactant: CCc1cc(N2CCCNCC2)c2ncccc2c1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc(N2CCCN(Cc3csc(-c4ccccc4)n3)CC2)c2ncccc2c1
Temperature: 60 °C
Yield: 51.3 %

Procedure:
A mixture of 8-[1,4]-diazepan-1-yl-6-ethylquinoline dihydrochloride (0.32 g, 1 mmol, 1 equiv), 4-chloromethyl-2-phenylthiazole (0.21 g, 1 equiv) and Cs2CO3 (1.63 g, 5 equiv) in 5 mL of DMF was heated at 60° C. for 3 hours and then cooled to room temperature. EtOAc (˜70 mL) was added and the mixture washed with saturated aqueous NaHCO3 (70 mL) and brine (70 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel flash column chromatography using 5% to 40% EtOAc in hexanes. Silica gel chromatography was repeated using 5% to 10% MeOH in EtOAc to afford the title compound as a light tan solid (0.22 g). 1H NMR (400 MHz, CD3OD) δ 8.65 (dd, 1H, J=1.8 and 4 Hz), 8.04 (dd. 1H, J=1.5 and 8.4 Hz), 7.91 (m, 1H), 7.90 (d, 1H, J=2.2 Hz), 7.41 (m, 3H), 7.36 (s, 1H), 7.31 (dd, 1H, J=4 and 8 Hz), 7.11 (s, 1H), 6.98 (s, 1H), 3.89 (s, 2H), 3.69 (m, 2H), 3.57 (t, 2H, J=5.87 Hz), 3.11 (m, 2H), 2.92 (t, 2H, J=5.3 Hz), 2.72 (q, 2H, J=7.0 Hz), 2.10 (m, 2H), 1.28 (t, 3H, J=7.0 Hz). MS (ES) m/z 429.2 (M+H+).
Reaction SMILES: Cl.[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH2:12])[CH2:9]2.[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[O:14].C(N(CC)CC)C.O>C(Cl)Cl>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:13]([N:15]1[CH2:19][CH2:18][N:17]=[CH:16]1)=[O:14])[CH2:9]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1C=NCC1
Yield: 93.4 %

Procedure:
A solution of 2-adamantylamine hydrochloride 3 g (15.98 mmol), carbonyldiimidazole 2.59 g (15.98 mmol), triethylamine 2.215 ml (15.98 mmol) in CH2Cl2 100 ml was stirred overnight at room temperature. Water was added, the organic phase separated, dried and concentrated to dryness yielding the title crude product 3.69 g (94%) as white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:21])[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:25]=1[C:26](O)=[O:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:21])[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:26]([C:25]1[C:29]([CH3:33])=[CH:30][CH:31]=[CH:32][C:24]=1[Cl:23])=[O:27]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cccn(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cccn(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Reaction time: 15 h
Yield: 88.8 %

Procedure:
To a suspension of 4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride salt (101 mg, 0.313 mmol), 2-chloro-6-methylbenzoic acid (60 mg, 0.35 mmol) and HBTU (133 mg, 0.35 mmol) in DMF (2 mL) was added DIEA (122 μL, 0.88 mmol) at room temperature. The resulting mixture was stirred for 15 h. Then, the mixture was poured into water (25 mL) and the organic compound was extracted into ethyl acetate (2×15 mL). The combined ethyl acetate extracts were washed successively with 0.5 N HCl (25 mL), saturated NaHCO3 solution (25 mL), brine solution (25 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography using a Biotage (40s) column to afford 122 mg (88% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester as an amorphous white solid. FAB-HRMS m/e calcd for C24H23ClN2O4 (M+H) 439.1425, found 439.1414
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([NH2:21])=[O:20])=[C:13]([OH:22])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][O:24]CCl.[CH3:27]N(C)C=O>>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([NH2:21])=[O:20])=[C:13]([O:22][CH3:27])[C:12]=1[O:24][CH3:23])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: COCCl
Reactant: NC(=O)CCc1ccc(OCc2ccccc2)cc1O
Agent: [H-]
Agent: [Na+]
Product: COc1c(CCC(N)=O)ccc(OCc2ccccc2)c1OC
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
To a stirred suspension of 5.64 g of 60% sodium hydride in oil in 628 mL of N,N-dimethylformamide was added 34.8 g of 3-(4-benzyloxy-2-hydroxyphenyl)propionamide under ice-cooling, and the mixture was stirred at 50° C. for 40 minutes. To the reaction mixture was added 12.39 g of chloromethyl methyl ether under ice-cooling, and the mixture was stirred at room temperature for 15 hours. After the reaction mixture was concentrated under reduced pressure to remove the solvent, the residue was poured into a mixture of 500 mL of ethyl acetate, 100 mL of toluene and 200 mL of water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a colorless solid. The solid was triturated in ethyl acetate-diisopropyl ether and collected by filtration to give 35.3 g of 3-(4-benzyloxy-2-methoxy-methoxyphenyl)propionamide as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23]Cl)[CH3:20]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:20][CH2:19][N:21]([CH2:25][CH3:26])[CH2:22][CH3:23]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
52.0 g (0.30 mol) of 2-chloro-4-nitrophenol is dissolved in 500 mL of DMF and 165 g (1.20 mol) of potassium carbonate is added batchwise. The mixture is stirred for 30 minutes at ambient temperature. Then 51.6 g (0.30 mol) of 2-diethylaminoethylchloride hydrochloride is added and the mixture is stirred for 3 days at ambient temperature. After this time, the mixture is filtered off, the solvent is eliminated, the residue is taken up in ethyl acetate, and washed with water. The organic phase is filtered through aluminum oxide (activity 2-3) and concentrated by evaporation. Yield: 41.0 g (50% of theory); Rf value: 0.60 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01); C12H17ClN2O3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[Na+].C([O-])(=O)C.[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][S:21]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: OCc1cccnc1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: O=S(=O)(Cc1cccnc1Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A chloroform (10 ml) solution of (2-chloropyridin-3-yl)methanol (204 mg, 1.42 mmol) and thionyl chloride (0.31 ml, 4.26 mmol) was stirred at 50° C. for 8.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in butanol (15 ml), followed by the addition of sodium 4-chlorobenzenesulfinate (423 mg, 2.13 mmol) and potassium acetate (418 mg, 4.26 mmol). The mixture was stirred at 70 to 80° C. for 15 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure, whereby the title compound (252 mg, 59%) was obtained as a white solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].C1C=CC=CC=1>O1CCCC1>[CH:1]1([NH:7][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[I:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)c1ccccc1I
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: O=C(NC1CCCCC1)c1ccccc1I

Procedure:
In accordance with the procedure of Example 3, 12.1 g of cyclohexylamine was reacted with 8.0 g of o-iodobenzoyl chloride in 20 ml of tetrahydrofuran. There was obtained by recrystallization from benzene 5.7 g of fine white crystals of N-cyclohexyl-o-iodobenzamide, m.p. 148°-149°, Rf 0.74.
Reaction SMILES: N1C=[CH:4][N:3]=[N:2]1.[CH2:6]([N:8](CC)CC)C.[CH3:13][N:14]([CH3:19])[S:15](Cl)(=[O:17])=[O:16]>C1(C)C=CC=CC=1>[CH3:13][N:14]([CH3:19])[S:15]([N:3]1[CH:4]=[N:8][CH:6]=[N:2]1)(=[O:17])=[O:16]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1c[nH]nn1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)n1cncn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 37.5 %

Procedure:
Triazole (5.08 g, 73.6 mmol) was dissolved in toluene (80 ml), and thereto were added triethylamine (9.52 ml, 68.4 mmol) and dimethylsulfamoyl chloride (10.6 ml, 73.6 mmol), and the mixture was stirred at 50° C. for 2 hours. The precipitates were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (4.52 g, 38%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:29])[CH:27]=[CH2:28])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[C:30]([N:13]1[CH2:12][CH2:11][N:10]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:29])[CH:27]=[CH2:28])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH2:15][CH2:14]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCNCC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.3 %

Procedure:
Diisopropylethylamine (0.24 ml, 1.36 mmol) was added in one portion to a stirred solution of N-[4-(piperazine-1-sulfonyl)-phenyl]-acrylamide (0.1 g, 0.34 mmol) in THF (5 ml). The mixture was stirred at room temperature for 5 minutes before benzoyl chloride (0.05 ml, 0.44 mmol) was added drop wise and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The crude reaction mixture was concentrated under vacuum and the residue was purified by Prep HPLC to give the title compound (0.018 g, 13% yield) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[C:23]([Cl:26])(=[O:25])[CH3:24]>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]2[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:1]=1.[C:23]([NH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])(=[O:25])[CH3:24]
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1C(=O)c1ccccc1
Product: Clc1cc(-c2ccccc2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-phenylquinoline was prepared by the following method (Rxn-1). 2-Aminobenzophenone (21 g, 106.5 mmol) was dissolved in methylene chloride (213 mL) and triethylamine (22.3 mL, 159.8 mmol) was added slowly. After cooling to 0° C., acetylchloride (8.3 mL, 117.2 mmol) was added to the reaction mixture dropwise. The reaction mixture was then removed from ice and allowed to stir overnight. Upon the addition of 10% hydrochloric acid (84 mL), the aqueous layers were combined and extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate, and concentrated. Purification by column chromatography (25% ethyl acetate/heptane) gave 2-acetamidobenzophenone.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:25][C@@H:26]1[NH:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32]>C(#N)C>[CH3:25][C@@H:26]1[N:31]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:6]=[N:5][N:4]=2)[CH2:30][CH2:29][NH:28][C:27]1=[O:32]
Reactant: C[C@@H]1NCCNC1=O
Reactant: FC(F)(F)c1ccc(-n2nnnc2CCl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H]1C(=O)NCCN1Cc1nnnn1-c1ccc(C(F)(F)F)cc1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[4-(trifluoromethyl)phenyl]-1H-tetrazole (500 mg, 1.90 mmol, commercially available from UkrOrgSynthesis, Kiev, Ukraine) in acetonitrile (8 mL) was added triethylamine (0.796 mL, 5.71 mmol) and (3S)-3-methyl-2-piperazinone (239 mg, 2.09 mmol, commercially available, for example from Sigma Aldrich, St Louis, USA). The reaction mixture was heated to 120° C. for 20 min. The reaction mixture was concentrated in vacuo and the crude product purified by reverse phase chromatography (Biotage SP4). The relevant fractions were combined, concentrated and dried in vacuo to yield the title compound as white crystals (349 mg).