Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([S:23](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:25])=[O:24])=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]2=[O:38])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[NH2:39][C:40]1[CH:44]=[CH:43][O:42][N:41]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[O:42]1[CH:43]=[CH:44][C:40]([NH:39][S:23]([C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:13]([C:4]2[C:3]([O:2][CH3:1])=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=2)[C:14](=[O:38])[CH:15]=[CH:16]3)(=[O:24])=[O:25])=[N:41]1
Reactant: Nc1ccon1
Reactant: COc1cc2ccccc2cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2ccccc2cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A solution of perfluorophenyl 1-(3-methoxynaphthalen-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.250 g, 0.457 mmol), 3-aminoisoxazole (0.037 ml, 0.502 mmol) and THF (4.57 ml) was cooled in an ice-bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF) (0.959 ml, 0.959 mmol) was added dropwise. After 60 min, the mixture was diluted with 1N aq. HCl and EtOAc. The aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was concentrated and then triturated with in Et2O. The resulting suspension was sonicated, then filtered. The collected solid was washed with Et2O (2×), dried under a stream of N2 (g), then dried under vacuum to give N-(isoxazol-3-yl)-1-(3-methoxynaphthalen-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.175 g, 0.391 mmol, 86% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.49-11.79 (m, 1H), 8.68-8.78 (m, 1H), 8.38-8.42 (m, 1H), 8.24-8.29 (m, 1H), 7.96-8.01 (m, 2H), 7.86-7.91 (m, 1H), 7.78-7.84 (m, 1H), 7.66 (s, 1H), 7.56-7.64 (m, 1H), 7.42-7.50 (m, 1H), 6.75-6.86 (m, 2H), 6.42-6.47 (m, 1H), 3.72-3.81 (m, 3H). m/z (ESI) 447.9 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[CH:6]=[CH:5][N:4]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>ClCCl.O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:12]2[CH:13]=[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=3)[CH:10]=[N:11]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CSc1nccc(-c2cn[nH]c2)n1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cn2cc(-c3ccnc(SC)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(methylthio)-4-(1H-pyrazol-4-yl)pyrimidine (200 mg, 1 mmol) in dichloromethane (3 mL) and H2O (1 mL) was added 4-methoxybenzylchloride (200 mg, 1.28 mmol) at 0° C. The mixture was stirred at RT overnight. The organic layer was separated, washed with brine and concentrated in vacuo to give crude 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine. 1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.50, (d, J=5.4 Hz, 1H), 8.16 (s, 1H), 7.40 (d, J=5.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 5.30 (s, 2H), 3.72 (s, 3H), 2.51 (s, 3H); MS (ESI) m/z: 313 (M+H+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][S:33]([C:30]4[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=4)(=[O:35])=[O:34])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 33.8 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (0.35 g, 1.08 mmol) and 4-methoxybenzenesulfonyl chloride (0.25 g, 1.19 mmol) in chloroform (5 ml) was added triethylamine (0.16 ml, 1.19 mmol) and the mixture was stirred at room temperature for 14 hours. The solvent was concentrated under reduced pressure. Water (20 ml) was added into the residue and the product was extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid and an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 0.18 g (34% yield) of the title compound. Melting point: 206-208° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[N:11]=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[O:9][N:8]=1.[CH:16](O)([CH2:18][CH3:19])[CH3:17]>>[CH3:6][C:7]1[N:11]=[C:10]([CH2:12][C:13]([O:15][CH:16]([CH2:18][CH3:19])[CH3:17])=[O:14])[O:9][N:8]=1
Reactant: CCC(C)O
Reactant: Cc1noc(CC(=O)O)n1
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(C)OC(=O)Cc1nc(C)no1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 36.4 %

Procedure:
Using the procedure of Example 17, 12 g of phosphorous oxychloride were slowly added to a mixture of 12 g of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 8.9 g of dry sec.-butanol and the rate of addition was adjusted to a reaction temperature of 65°±5° C. The resulting reaction mixture was stirred for 90 minutes at 65° C., and then treated as in Example 17. The product was distilled at 68° C. and 1.5 mm Hg to obtain 6.1 g (35% yield) of sec.-butyl 3-methyl-1,2,4-oxadiazol-5-yl-acetate. The purity of the final product was about 95% (according to TLC and PMR spectrum) and it had a refractive index nD25 =1.438.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[O:11]1[CH:13]([CH3:14])[CH2:12]1>>[OH:11][CH:13]([CH3:14])[CH2:12][NH:4][C:3]1[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=1[CH3:1]
Reactant: CC1CO1
Reactant: Cc1cc(C)c(N)c(C)c1
Product: Cc1cc(C)c(NCC(C)O)c(C)c1
Yield: 45.1 %

Procedure:
2,4,6-Trimethylaniline is reacted with 1,2-epoxypropane as described in Example 3, Method (b), point (a) to obtain N-(β-hydroxy-propyl)-2,4,6-trimethyl-aniline with a yield of 45.1%, b.p.: 130°-135° C./0.4 mm Hg.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:12]=2[CH:13]=1>N1C=CC=CC=1>[CH3:6][N:7]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:25][CH:26]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([NH:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[CH:14][C:12]=2[CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCc1ccc(N)cc1)Cc1cc2ccc(N)cc2o1
Solvent: c1ccncc1
Product: CN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1cc2ccc(NS(C)(=O)=O)cc2o1

Procedure:
Methanesulphonyl chloride (0.21 g, 1.8 mmole) and N-methyl-N-(6-aminobenzofur-2-ylmethyl)-4-aminophenethylamine (see Preparation 2--0.24 g, 0.82 mmole) in pyridine (3 ml) when reacted together under conditions similar to those of Example 2, gave the title compound as an oil, yield 0.18 g.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[S:12](Cl)(=[O:15])(=[O:14])[NH2:13].Cl>O1CCCC1.O>[S:12]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:11][S:12](=[O:15])(=[O:14])[NH2:13])(=[O:15])(=[O:14])[NH2:13]
Reactant: OCCCCCCCO
Reactant: NS(=O)(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)OCCCCCCCOS(N)(=O)=O
Yield: 63.1 %

Procedure:
A 57% oil dispersion of sodium hydride (11.8 g, 0.28 mole NaH) was added to 150 ml of tetrahydrofuran. The suspension was stirred and gently heated, and 15.84 g (0.12 mole) of 1,7-heptanediol in 75 ml of tetrahydrofuran was added gradually over a period of 90 minutes. An additional 25 ml of tetrahydrofuran was then added, and the reaction mixture was stirred at reflux for five hours. An additional 150 ml of tetrahydrofuran was added, and to the stirred warm mixture there was added dropwise a solution of 28.9 g (0.25 mole) of sulfamoyl chloride in 150 ml of tetrahydrofuran over a two hour period. The reaction mixture was stirred at reflux for five hours, then cooled and treaated dropwise with 125 ml of water. The mixture was acidified with 2N hydrochloric acid, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue triturated with ethyl acetate to give a yellow solid which was recrystallized from an ethyl acetate--hexane mixture to give 22.0 g of 1,7-heptanediol disulfamate as colorless granules, m.p. 87°-88° C.
Reaction SMILES: CC1CC(OC([N:11]2[CH:16]=[C:15]([Si](C(C)C)(C(C)C)C(C)C)[C:14](=[O:27])[CH2:13][CH:12]2[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=O)C(C(C)(C2C=CC=CC=2)C)CC1.C[O-].[Na+].C(O)(=O)C(O)=O>CO>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C@@H:12]2[CH2:13][C:14](=[O:27])[CH:15]=[CH:16][NH:11]2)=[CH:29][CH:30]=1
Reactant: CC1CCC(C(C)(C)c2ccccc2)C(OC(=O)N2C=C([Si](C(C)C)(C(C)C)C(C)C)C(=O)CC2c2ccc(F)cc2)C1
Agent: C[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CO
Product: O=C1C=CN[C@H](c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
To a solution of 2-(4-fluoro-phenyl)-4-oxo-5-triisopropylsilanyl-3,4-dihydro-2H-pyridine-1-carboxylic acid 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyl ester (7.78 g, 12.8 mmol) in methanol (95 mL) was added 25% sodium methoxide in methanol (29.4 mL, 128.4 mmol). The mixture was heated at reflux for 16 h. After cooling to rt, oxalic acid (46.3 g, 512 mmol) was added and the mixture was stirred for 2 h. The solvent was evaporated to dryness. The crude was partitioned between ethyl acetate and water. The organic layer was washed with water, brine dried over MgSO4, filtered and concentrated to dryness. Purification by flash chromatography (hex:EtOAc/2:8-0:1) gave (S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (0.886 g, 36%, ee 99.3%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.[Li]CCCC.Cl>C1COCC1>[CH3:12][NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([B:13]([OH:18])[OH:14])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(B(O)O)cc1
Temperature: 0 °C
Yield: 104.6 %

Procedure:
To a solution of 4-bromo-N-methyl-benzene sulfonamide (24.9 g, 0.1 mol) and B(OiPr)3 (28.2 g, 0.15 mol) in THF (200 mL) was added n-BuLi (100 mL, 0.25 mol) at −70° C. The mixture was slowly warmed to 0° C., then 10% HCl solution was added until pH 3˜4. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, and evaporated under reduced pressure to give 4-(N-methylsulfamoyl)phenylboronic acid (22.5 g, 96%), which was used in the next step without further purification. 1H NMR (DMSO-d6, 300 MHz) δ 8.29 (s, 2 H), 7.92 (d, J=8.1 Hz, 2 H), 7.69 (d, J=8.4 Hz, 2 H), 2.36 (d, J=5.1 Hz, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][O:13][C:14](=[O:24])[C@@H:15]([NH:17][CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21])[CH3:16].C(=O)([O-])O.[Na+]>CC(C)=O.O>[CH3:12][O:13][C:14](=[O:24])[C@@H:15]([N:17]([C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])[CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21])[CH3:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@H](C)NCC(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)[C@H](C)N(CC(OC)OC)C(=O)OCc1ccccc1
Yield: 72.4 %

Procedure:
Benzyl chloroformate (4.46 g, 24.8 mmol) was added at 0° C. to a mixture of (S)-2-(2,2-dimethoxy-ethylamino)-propionic acid methyl ester (4.75 g, 24.8 mmol) and sodium hydrogencarbonate (4.17 g, 49.7 mmol) in acetone (25 mL) and water (25 mL). The ice bath was removed, then after 2 h the reaction mixture was poured onto ice water and extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-EtOAc gradient) afforded the title compound (5.84 g, 72%). Yellow oil, MS (ISP)=348.2 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[O:17]1[CH:19]([CH:20]([OH:22])[CH3:21])[CH2:18]1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][CH2:21][CH:20]([OH:22])[CH:19]([OH:17])[CH3:18])=[CH:9][CH:8]=1
Reactant: Nc1ccc(OCc2cccc(Cl)c2)cc1
Reactant: CC(O)C1CO1
Solvent: CC(C)O
Product: CC(O)C(O)CNc1ccc(OCc2cccc(Cl)c2)cc1
Yield: 50.3 %

Procedure:
A solution containing 50 g (0.21 mol) of 4-(3'-chlorobenzyloxy) aniline and 21.6 g (0.24 mol) of the mixture obtained in Example 1 in 850 ml of isopropanol is refluxed for 6 hrs 30 mins. When the isopropanol has evaporated, the crude mixture is purified by flash silica chromatography (eluant: CH2Cl2 --CH3OH: 97-3). 34 g (yield: 49%) of white solid is recovered, corresponding to the product expected and having a melting point of from 95°-96° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[N+:10]([C:13]1[CH:18]=[CH:17][C:16](Cl)=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21])([O-:12])=[O:11]>C(O)C.[Cu]>[F:21][C:20]([F:22])([F:23])[C:14]1[CH:15]=[C:16]([N:4]2[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]2=[O:7])[CH:17]=[CH:18][C:13]=1[N+:10]([O-:12])=[O:11]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Agent: [Cu]
Solvent: CCO
Product: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Temperature: 200 °C

Procedure:
71.5 grams of copper in powder form were added to 96.10 grams of 5,5-dimethyl-hydantoin and 170.86 grams of 2-nitro-5-chloro trifluoromethylbenzene. The mixture was heated to 200° C. for about 21 hours, the pressure being maintained at 450 millibars, then, was cooled to 20° C. and taken up in 480 ml of ethanol. The product was characterized and determined by thin layer chromatography of the ethanol solution.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:31]([Cl:34])=[CH:32][N:33]=1)[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]2[CH2:12][CH2:13][C:14]3[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:18]=3[C:10]=2[CH:9]=1)=[O:6].[CH3:35][N:36]1[CH2:42][CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:34][C:31]1[C:4]([C:5]([NH:7][C:8]2[CH:30]=[CH:29][C:11]3[CH2:12][CH2:13][C:14]4[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=5)[C:18]=4[C:10]=3[CH:9]=2)=[O:6])=[CH:3][C:2]([N:39]2[CH2:40][CH2:41][CH2:42][N:36]([CH3:35])[CH2:37][CH2:38]2)=[N:33][CH:32]=1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Reactant: CN1CCCNCC1
Product: CN1CCCN(c2cc(C(=O)Nc3ccc4c(c3)-c3c(c(C(N)=O)nn3-c3ccc(F)cc3)CC4)c(Cl)cn2)CC1
Reaction time: 24 h
Yield: 78.3 %

Procedure:
The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 248 (1 g, 0.0020 mol) and 1-methylhomopiperazine (4.6 g, 0.040 mol). The reaction was run at 95° C. for 24 h. After allowing the reaction mixture to cool, the volatiles were removed under vacuum. The residue was triturated with H2O to yield 0.899 g of the title compound as a tetrahydrate (yield: 71%). 1H NMR (300 MHz, d6-DMSO): δ 1.81-1.83 (m, 2H), 2.21 (s, 3H), 2.41 (t, 2H, J=5.5 Hz), 2.53 (t, 2H, J=4.56 Hz), 2.87-2.93 (m, 4H), 3.53 (t, 2H, J=5.5 Hz), 3.63-3.67 (m, 2H), 6.62 (s, 1H), 7.19 (d, 1H, J=1.9 Hz), 7.27-7.38 (m, 4H), 7.42-7.45 (dd, 1H, J=8.12 Hz, 1.88 Hz), 7.53-7.58 (m, 3H), 8.07 (s, 1H), 10.31 (s, 1H). M+1=575.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[O:12]=[C:13](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[N:8]([CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[C:13]=[O:12]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NCc1cccc([N+](=O)[O-])c1
Solvent: C1COCCO1
Product: O=C=NCc1cccc([N+](=O)[O-])c1
Temperature: 75 °C
Reaction time: 3 h
Yield: 126.4 %

Procedure:
3-Nitro-benzylamine (2.3 g, 15.1 mmol) was dissolved in anhydrous dioxane (50 ml) under N2 atmosphere. Diphosgene (2.2 ml, 18.2 mmol) was added, a precipitate formed which dissolved upon heating to 75° C. The reaction was stirred at 75° C. for 3 h, cooled and evaporated to dryness giving 3.4 g of crude material which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][CH:3]([C:4]=23)[C:2]1=[O:13].[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:3]12[CH2:12][CH2:11][CH2:10][C:5]3[C:4]1=[C:9]([CH:8]=[CH:7][CH:6]=3)[NH:1][C:2]2=[O:13]
Reactant: BrCCCCCBr
Reactant: O=C1Nc2cccc3c2C1CCC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCCCBr)CCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.1 %

Procedure:
2a, 3,4,5-Tetrahydrobenz [cd]indole-2(1H) -one (1.0 g, 5.8 mmol) was dissolved in anhydrous N,N-dimethylformamide (40 ml). Thereto was added sodium hydride (250 mg, 6.3 mmol), and the resulting solution was stirred at a room temperature for 1 hour. The reaction solution was mixed with 1,5-dibromopentane (2.4 ml, 17 mmol) and again stirred for 17 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate and water. The reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 230 mg of the title compound (0.70 mmol, 12% in yield).
Reaction SMILES: N1(CC[CH2:8][NH:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:42]=[CH:41][C:32]5[O:33][C:34]([F:40])([F:39])[O:35][C:36]([F:38])([F:37])[C:31]=5[CH:30]=4)=[O:27])=[CH:21][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[O:11])C=CN=C1.NC[CH2:45][CH2:46][N:47]1[CH:51]=[CH:50]N=[CH:48]1>>[N:47]1([CH2:48][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:42]=[CH:41][C:32]5[O:33][C:34]([F:39])([F:40])[O:35][C:36]([F:37])([F:38])[C:31]=5[CH:30]=4)=[O:27])=[CH:21][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[O:11])[CH2:46][CH2:45][CH2:50][CH2:51]1
Reactant: O=C(Nc1ccc(Oc2ccnc(C(=O)NCCCn3ccnc3)c2)cc1)Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Reactant: NCCCn1ccnc1
Product: O=C(Nc1ccc(Oc2ccnc(C(=O)NCCN3CCCC3)c2)cc1)Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2

Procedure:
The title compound was prepared in the same manner described for N-[3-(1H-imidazol-1-yl)propyl]-4-[4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}-amino)phenoxy]pyridine-2-carboxamide, substituting 1-(2-aminoethyl)pyrrolidone for 1-(3-aminopropyl)imidazole. 1H-NMR (MeOH-d4) δ 8.45 (d, 1H), 8.00 (d, 1H), 7.65 (dd, 1H), 7.56 (m, 3H), 7.22 (d, 1H), 7.10 (m, 2H), 7.04 (dd, 1H), 3.57 (t, 2H), 2.77 (t, 2H), 2.67 (m, 4H), 1.83 (m, 4H); MS LC-MS [M+H]+=576.2, RT=3.16 min.
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[NH:6])(=[O:3])[CH3:2].[H-].[Na+].[CH2:10]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[C:25](OCC)=[S:26])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[C:25]([NH:6][C:5]([NH2:7])=[N:4][C:1](=[O:3])[CH3:2])=[S:26])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=S)C1CCCN1C(=O)OCc1ccccc1
Reactant: CC(=O)NC(=N)N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N=C(N)NC(=S)C1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 55.8 %

Procedure:
1-Acetylguanidine (7.20 g, 71.0 mmol) was dissolved in THF (100 mL). The solution was cooled to 0° C. and NaH (1.90 g, 80.0 mmol) was added to the reaction in small batches over 5 mins. Next, 2-ethoxythiocarbonyl-pyrrolidine-1-carboxylic acid benzyl ester (19.6 g, 66.9 mmol) in THF (50 mL) was added to the reaction dropwise over 30 minutes while maintaining the temperature between 0-5° C. The reaction was allowed to return to room temperature, while stirring an additional 12 hours. The product was precipitated by addition of petroleum ether. The organic layer was decanted off and the solid was retained and redissolved in water (300 mL). The pH was adjusted to pH=3 by addition of acetic acid. The resulting solution was transferred to a separatory funnel and extracted with DCM (3×250 mL). The organic layers were combined, dried over MgSO4 and concentrated under vacuo to afford 13.0 g (56%) of 2-(N′-acetyl-guanidinocarbothioyl)-pyrrolidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]#[N:22])[C:9]=2[CH3:23])=[CH:4][CH:3]=1.[CH:24]1([C:29]([NH:31][NH2:32])=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].CO>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:22]=[C:29]([CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[NH:31][N:32]=3)[C:9]=2[CH3:23])=[CH:6][CH:7]=1
Reactant: NNC(=O)C1CCCC1
Reactant: Cc1c(C#N)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CO
Product: Cc1c(-c2n[nH]c(C3CCCC3)n2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonitrile (300 mg, 0.83 mmol), cyclopentanecarbohydrazide (116 mg, 0.90 mmol) and potassium carbonate (57 mg, 0.41 mmol) dissolved in 1-butanol (2 ml) was placed in a sealed tube, stirred at room temperature for 10 minutes and then refluxed at 150° C. for 1 day. The mixture was cooled down to room temperature and methanol (4 ml) was added thereto, followed by filtering. The filtrate was purified by reverse phase preparative HPLC, to obtain the title compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=[O:5].[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[N:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2.[OH-].[K+]>CO>[Br:13][C:14]1[CH:15]=[C:16]2[C:17]([CH:4]([C:3]3[C:6]([O:11][CH3:12])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=3[Cl:1])[OH:5])=[CH:18][NH:19][C:20]2=[N:21][CH:22]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: COc1ccc(F)c(Cl)c1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)c(Cl)c1C(O)c1c[nH]c2ncc(Br)cc12

Procedure:
A solution of 2-chloro-3-fluoro-6-methoxybenzaldehyde (10.55 g, 55.82 mmol), 5-bromo-7-azaindole (10.0 g, 50.76 mmol) and KOH (4.0 g, 71 mmol) in methanol (200 mL) was stirred at ambient temperature for 12 h. The reaction mixture was quenched with water and the crystallizing solid was filtered and dried to give the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): □ δ=3.71 (s, 3H), 5.69 (d, 1H, J=6.3 Hz), 6.55 (d, 1H, J=4.5 Hz), 7.07 (dd, 1H, J=4.5, 4.2 Hz), 7.19 (s, 1H), 7.32 (t, J=8.0 Hz), 8.30 (s, 1H), 9.60 (s, 1H), 11.38 (s, br, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(Br)ccc1CO
Reaction time: 4 h
Yield: 80.4 %

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid (1.0 g, 4.65 mmol) in Et2O (15 mL) was added lithium aluminiumhydride (370 mg, 10.23 mmol) and the mixture was stirred for 4 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (4×100 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica, petrol ether/EtOAc) to give the title compound as a colorless gum (752 mg, 80%). 1H NMR (CDCl3, 400 MHz) δ 7.35-7.30 (2H, m), 7.24 (1H, m), 4.65 (2H, s), 2.32 (3H, s).