Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH2:15]([N:17](CC)CC)[CH3:16].O1CCCC1.C(N)C>C(OCC)(=O)C.CCCCCCC>[CH2:11]([O:10][C:8]([C:7]1[C:2]([NH:17][CH2:15][CH3:16])=[N:3][C:4]([S:13][CH3:14])=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: CCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCNc1nc(SC)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A 22-L, 4-necked round-bottomed flask was equipped with a mechanical stirrer, a dropping funnel, and a thermometer. The flask was charged with the ethyl 4-chloro-2-(methylthio)-5-pyrimidinecarboxylate (1.53 kg, 6.56 mol), triethylamine (2.74 L, 19.7 mol, 3 eq), and 7.5 L of tetrahydrofuran to give a solution. The aqueous ethylamine (0.53 L, 6.56 mol, 1 eq) was added via the dropping funnel over 20 minutes. The reaction temperature rose to 35° C. during the addition. The reaction was stirred at ambient temperature for 2 hours. The reaction was checked for completion using TLC (SiO2; 7:3/heptane:ethyl acetate). The precipitate (triethylamine hydrochloride) was filtered off and washed 2 times with tetrahydrofuran, combining the washes with the original filtrate. The tetrahydrofuran was stripped to near dryness on a rotary evaporator. The residue was partitioned between saturated aqueous sodium bicarbonate (500 mL) and ethyl acetate (1 L). Note that there is carbon dioxide gas evolution from the bicarbonate both during the partitioning and the subsequent washes. The layers were separated and the organic layer washed 2 times with saturated aqueous sodium bicarbonate and 1 time with brine. The solution was dried over magnesium sulfate, filtered, and stripped to give the titled compound as an off-white solid. Yield: 95%.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([CH3:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])(=O)=O.[F:17][C:18]([F:30])([F:29])[CH2:19][CH2:20][S:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:15][C:9]([F:14])([C:10]([F:11])([F:12])[F:13])[CH:8]([CH3:16])[CH2:7][CH2:6][CH:24]([S:21]([CH2:20][CH2:19][C:18]([F:29])([F:30])[F:17])(=[O:23])=[O:22])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: CC(CCOS(C)(=O)=O)C(F)(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(CCC(C)C(F)(F)C(F)(F)F)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 168 h
Yield: 16.9 %

Procedure:
To a solution of 2.0 g of 4,4,5,5,5-pentafluoro-3-methyl-pentyl methanesulfonate and 1.7 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide was added 1.0 g of potassium carbonate at room temperature, heated to 60° C. and then stirred at the same temperature for 7 days. The reaction mixture was allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.5 g of methyl 6,6,7,7,7-pentafluoro-5-methyl-2-(3,3,3-trifluoropropylsulfonyl)heptanoate, which was dissolved in 20 ml of tetrahydrofuran. To the solution was added 0.1 g of sodium hydride (60% in oil) at room temperature. The reaction mixture was stirred at the same temperature for 0.5 hours. To the reaction mixture was added 0.2 g of N-chlorosuccinimide at room temperature, and then stirred for 2 hours. Thereto was added 10% hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was dissolved in 20 ml of methanol. To the solution was added 0.5 ml of ammonia (7M methanol solution) at room temperature, and then stirred at the same temperature for 30 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.22 g of 2-chloro-6,6,7,7,7-pentafluoro-5-methyl-2-(3,3,3-trifluoropropylsulfonyl)heptanamide (hereinafter referred to as the present compound (31)).
Reaction SMILES: [CH3:1][CH:2]([C:8](=O)[CH2:9][C:10](=O)[CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:14][NH2:15]>C1COCC1.O>[CH3:11][C:10]1[CH:9]=[C:8]([CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[NH:15][N:14]=1
Reactant: CCOC(=O)C(C)C(=O)CC(C)=O
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)c1cc(C)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.4 %

Procedure:
To a solution of 18.6 g (100. mmol) of ethyl 2-methyl-3,5-dioxohexanoate from step A in 200 mL of THF and 50 mL of water was added 3.45 mL (110 mmol) of anhydrous hydrazine. The biphasic reaction mixture was stirred at ambient temperature overnight then evaporated to dryness in vacuo. The crude yellow residue was dissolved in an ethyl acetate and water mixture and flushed through a 50 g silica gel plug. The filtrate was then evaporated to dryness in vacuo and the residue purified by silica gel chromatography eluting with a 0-100% ethyl acetate in hexanes gradient to afford the title compound as a yellow oil (1.89 g, 10%). 1H NMR (CDCl3, 500 MHz) δ 7.26 (s, 1H), 5.98 (s, 1H), 4.20-4.12 (m, 2H), 3.81 (q, J=7.3 Hz, 1H), 2.28 (s, 3H), 1.51 (d, J=7.3 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H). LC-MS: m/z (ES) 183 (MH)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13](=[O:19])[CH2:14][C:15](=[O:18])[CH2:16][CH3:17])[CH3:11]>>[CH2:10]([O:12][C:13](=[O:19])[CH:14]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)[C:15](=[O:18])[CH2:16][CH3:17])[CH3:11]
Reactant: CCOC(=O)CC(=O)CC
Reactant: Fc1ccc(CBr)cc1
Product: CCOC(=O)C(Cc1ccc(F)cc1)C(=O)CC

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-4-fluorobenzene and 3-oxopentanoic acid ethyl ester.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:15](C(OC(C)(C)C)=O)[C:9]2=[N:10][CH:11]=[C:12](O)[CH:13]=[C:8]2[CH:7]=1)=[O:5].[CH2:23](N(CC)CC)C.FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+].C[Al](C)C>ClCCl.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.O.C(OCC)(=O)C>[CH2:2]([O:3][C:4]([C:6]1[NH:15][C:9]2=[N:10][CH:11]=[C:12]([CH3:23])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(O)cnc2n1C(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Al](C)C
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(C)cnc2[nH]1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
A solution of 4.0 g (13.1 mmol) 5-hydroxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 100 mL dichloromethane was cooled to 0° C. and 2.2 mL (1.6 g, 15.7 mmol) triethylamine and 2.6 mL (4.4 g, 15.7 mmol) trifluoromethanesulfonic acid were added. After 2 h at 0° C. the reaction was poured into 10% aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in 100 mL tetrahydrofuran and 0.75 g (0.65 mmol) tetrakis(triphenylphosphine)palladium (0) and 13.1 mL trimethylaluminium (2M solution in n-heptane) were added. The reaction mixture was heated to reflux for 2 h and after cooling to room temperature poured into ethyl acetate and water, filtered through speedex and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography over silica gel (0.030–0.063 mm) with ethyl acetate:n-hexane (1:1) as eluant to give the product as a light yellow solid (64.5%).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH:18]3[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]3)[CH:13]=2)[O:8]1.[CH3:26][N:27]1[C:31]([CH3:32])=[C:30]([CH2:33][NH2:34])[C:29]([CH3:35])=[N:28]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH:18]3[CH2:23][CH2:22][CH:21]([NH:34][CH2:33][C:30]4[C:29]([CH3:35])=[N:28][N:27]([CH3:26])[C:31]=4[CH3:32])[CH2:20][CH2:19]3)[CH:13]=2)[O:8]1
Reactant: Cc1nn(C)c(C)c1CN
Reactant: Cc1ccccc1C1CCc2cc(OC3CCC(=O)CC3)ccc2O1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccccc1C1CCc2cc(OC3CCC(NCc4c(C)nn(C)c4C)CC3)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 100 mg 4-(2-o-tolyl-chroman-6-yloxy)-cyclohexanone (0.30 mmol) in 2 ml of methanol and 0.15 ml of acetic acid at room temperature 124 mg (1,3,5-trimethyl-1H-pyrazol-4-yl-methyl)amine (0.89 mmol) and 56 mg of sodium cyanoborohydride (0.89 mmol) were added in one portion and stirring at room temperature was continued for 2 h. Volatile components were removed under reduced pressure and the resulting residue dissolved in dichloromethane. The organic layer was washed with aqueous 2N sodium hydroxide solution and saturated aqueous sodium chloride solution. The organic layer was dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by reversed phase HPLC. 132 mg of the title compound were isolated.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Br:24][CH2:25][CH2:26][CH2:27]Br>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC>[Br:24][CH2:25][CH2:26][CH2:27][O:23][CH2:22][CH2:21][CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: BrCCCBr
Reactant: CCCCCCCCCCCCCCCCCCOCCCO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Product: CCCCCCCCCCCCCCCCCCOCCCOCCCBr
Yield: 7.7 %

Procedure:
Employing 3-(octadecyloxy)propanol (5 g), 1,3-dibromopropane (9.2 g) and cetyltrimethylammonium chloride (0.97 g), a reaction and aftertreatment are conducted in the same manner as those in Reference Example 4 to obtain the above-titled compound (0.53 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[F:18][C:19]([F:29])([F:28])[C@H:20]([NH2:27])[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:27][C@H:20]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[C:19]([F:18])([F:28])[F:29])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: N[C@H](c1cccnc1)C(F)(F)F
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: O=C(N[C@H](c1cccnc1)C(F)(F)F)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (R)-2,2,2-trifluoro-1-pyridin-3-yl-ethylamine (CAN 1212813-98-3) as starting materials, MS (EI): m/e=392.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:13][O:14][CH3:15])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=[O:7].[OH-].[K+].Cl>>[CH3:1][O:2][C:3]1[C:4]([CH2:13][O:14][CH3:15])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COCc1c(OC)cccc1C(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COCc1c(OC)cccc1C(=O)O
Reaction time: 16 h
Yield: 91.4 %

Procedure:
To a 100 mL flask containing 10.1 g (0.039 mol) of methyl 2-bromomethyl-3-methoxybenzoate in 50 mL of CH3OH, were added 19 g of a 25% wt. solution of NaOMe (4.74 g, 0.087 mol). The reaction was stirred at room temperature for 2 hours and then evaporated on a rotary evaporator to remove the CH3OH. About 200 mL of water were added to the residue and the resulting solution was extracted with CHCl3. The CHCl3 extract was dried and evaporated to yield 6.27 g of crude methyl 3-methoxy-2-methoxymethylbenzoate (77% yield). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7-7.4 (multiple, 3H), 4.783 (s, 2H), 3.897 (s, 3H), 3.864 (s, 3H), 3.37 (s, 3H). 6.27 g of methyl 3-methoxy-2-methoxymethylbenzoate was stirred with a 20% aqueous KOH solution (6.7 g, 0.12 mol in 34 g of solution) at 50° C. in an oil bath for 4-5 hours, and then at room temperature for 16 hours. The reaction mixture was acidified with 3N HCl to pH 2 and extracted with CH2Cl2. The CH2Cl2 extract was dried and evaporated to yield 5.35 g of 3-methoxy-2-methoxymethylbenzoic acid (92% yield). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.65 (1H, d), 7.40 (t, 1H), 7.10 (d, 1H), 4.83 (s, 2H), 3.88 (s, 3H), 3.46 (s, 3H).
Reaction SMILES: S([O-])([O-])=O.[C:5](=[O:8])([O-])[O-].[K+].[K+].[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1)(=[O:13])[CH3:12]>CN(C)C=O>[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:8][CH3:5])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(NC(C)=O)cc1
Temperature: 100 °C
Yield: 138.4 %

Procedure:
To a three-necked 100 ml flask equipped for reflux and fitted with a mechanical stirrer was added 10 ml (0.12 mol) of diemthyl sulfite, 2.0 g (0.014 mol) of potassium carbonate, 10 ml dimethylformamide and 5.0 g (0.033 mol) of p-acetamidophenol. The mixture was heated to 100° C. for six hours then quenched while hot with 200 ml of water. The solution was made basic with dilute caustic and the organic materials were extracted into methylene chloride. The extracts were concentrated in vacuo to give 3.2 g of p-acetamidoanisole.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:6])=O.CN(C)C=O.N1C=CC=CC=1.C1(S(Cl)(=O)=O)C=CC=CC=1>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Cl
Yield: 89.3 %

Procedure:
Further, 2-chloro-5-nitrobenzamide (100 g) was added to dimethylformamide (240 ml) and pyridine (100 ml). To the mixture was dropwise added benzenesulfonyl chloride at room temperature with stirring, and the mixture was stirred at 145° C. for 3 h. The reaction mixture was ice-cooled, and water (240 ml) was added thereto. The precipitated crystals were recrystallized from hydrous ethanol to give 2-chloro-5-nitrobenzonitrile (81.3 g), melting point: 108–110° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:13])[C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1.Br[CH2:15][CH2:16][CH2:17][CH3:18]>O1CCCC1>[CH2:15]([O:13][CH2:3][C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCBr
Reactant: OCc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOCc1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
4 g of sodium hydride (60%) and 100 ml of tetrahydrofuran (THF) were stirred in a nitrogen stream. Thereto was dropwise added, in 30 minutes, 15.2 g (0.1 mol) of piperonyl alcohol dissolved in 70 ml of THF, followed by stirring for 30 minutes. Thereto was dropwise added 13.7 g (0.1 mol) of 1-bromobutane dissolved in THF, followed by stirring for 12 hours. The stirring was stopped and the reaction mixture was concentrated. The concentrate was dropped into an excess amount of a 2 N aqueous hydrochloric acid solution. Heptane was added thereto for extraction. The extract was washed with water until the washings became neutral, and then concentrated. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to obtain 8.0 g of piperonyl butyl ether at a yield of 38.5% as a transparent oily substance.
Reaction SMILES: FC1C=CC([C@@H]([C:10]2[N:19]=[C:18](NC3C=C(C)NN=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)O)=CC=1.FC1C=CC(C(C2N=C([NH:46][C:47]3[CH:51]=[C:50](C)[NH:49][N:48]=3)C3C(=CC=CC=3)N=2)O)=CC=1>>[NH:49]1[CH:50]=[CH:51][C:47]([NH:46][C:10]2[N:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[N:48]1
Reactant: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Reactant: Cc1cc(Nc2nc([C@@H](O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Product: c1ccc2nc(Nc3cc[nH]n3)ncc2c1

Procedure:
or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. (S)-(4-Fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol was determined to be the (−) isomer of (4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol by optical rotation analysis.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH2:20])=[N:16][CH:17]=1>>[F:9][C:5]1[CH:4]=[CH:3][C:2]([NH:20][CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:22])([F:10])[F:21])=[CH:17][N:16]=2)=[CH:7][C:6]=1[CH3:8]
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: Cc1cc(Br)ccc1F
Product: Cc1cc(NCCc2ccc(C(F)(F)F)cn2)ccc1F

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-fluoro-3-methyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 299.3 [M+H]+) was prepared from 5-bromo-2-fluorotoluene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-])=O>C(O)(=O)C.C(=O)(O)[O-].[Na+].[Fe]>[NH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Cl)c(N)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A solution of methyl 4-chloro-3-nitrobenzoate (10 g) dissolved in acetic acid (100 mL) was treated with Iron powder (10.36 g) under nitrogen. The resulting mixture was stirred vigorously at 20° C. for 2 h. The reaction mixture was filtered through celite and the filtrate evaporated to dryness to afford crude product. The residue was diluted with aqueous sodium bicarbonate solution (200 mL), and extracted with dichloromethane (250 mL). The organic layer was separated, dried (MgSO4), filtered and evaporated to afford the sub title compound (8.41 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[C:8]=2[CH:18]=1)([O-])=O.C(O)CC.Cl.[Sn]>O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[C:8]=2[CH:18]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)c1ccccc1-2
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: CCCO
Product: Nc1ccc2c(c1)S(=O)(=O)c1ccccc1-2
Temperature: 25 °C
Yield: 93 %

Procedure:
A 3 L round-bottom-flask equipped with a stirring bar, reflux condenser, and gas inlet was charged with 3-nitro-dibenzothiophene-5,5-dioxide (26 g, 0.1 mol), n-propanol (280 mL), water (840 mL), concentrated hydrochloric acid (325 mL), and tin powder, 20 mesh (65 g, 0.55 mol) then purged with nitrogen. The slurry was heated to a reflux overnight, which led to the consumption of the yellow crystals. The hot solution was filtered to remove the remaining tin powder then cooled to room temperature and chilled in an ice bath to crystallize the product. The yellow crystals were collected by vacuum filtration without washing with water then air dried. The crystals were added to a 10% solution of sodium hydroxide (200 mL) to liberate the free amine from the hydrochloride salt. The yellow powder was collected by vacuum filtration, washed well with water, then dried under vacuum to give 21.5 g of 3-amino-dibenzothiophene-5,5-dioxide (93% yield).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][C:27]=1[CH3:38].[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][N:35]([C:47](=[O:48])[CH2:46][N:43]3[C:44]([CH3:45])=[C:40]([Cl:39])[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42]3)[CH2:34][CH2:33]2)=[CH:28][C:27]=1[CH3:38]
Reactant: Cc1cc(N2CCNCC2)ccc1Cl
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)ccc1Cl

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chloro-3-methylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.25 (d, 1H), 7.05 (s,1H), 6.90 (d, 1H), 5.38 (s, 2H), 3.64 (m, 4H), 3.27 (m, 2H), 3.17 (m, 2H), 2.26 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=435.1, found=435.0.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=[O:11].[F:13][C:14]1[CH:15]=[C:16]([SH:20])[CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>O>[F:13][C:14]1[CH:15]=[C:16]([S:20][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)CCc1ccccc1I
Reactant: Fc1cccc(S)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCc1ccccc1Sc1cccc(F)c1

Procedure:
3-(2-Iodo-phenyl)-propionic acid (0.3 g, 1.1 mmol) was dissolved in water (2.8 mL). 3-Fluoro-benzenethiol (0.13 g, 0.99 mmol), KOH (0.15 g, 2.6 mmol) and Cu (13 mg, 0.2 mmol) was added. The mixture was refluxed overnight. The hot solution was filtered and the filtrate was made acidic with concentrated HCl. The mixture was extracted with dichloromethane (2×25 mL). The combined organic phases were washed with water (15 mL), dried (MgSO4), filtered and evaporated. Yield: 0.26 g, 96%.
Reaction SMILES: O.NN.[F:4][C:5]([F:19])([F:18])[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([OH:16])[CH:10]=[N+:9]2[O-].[OH-].[Na+]>>[F:19][C:5]([F:4])([F:18])[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([OH:16])[CH:10]=[N:9]2
Reactant: [O-][n+]1cc(O)nc2ccc(C(F)(F)F)cc21
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cnc2cc(C(F)(F)F)ccc2n1
Reaction time: 5 h
Yield: 93.9 %

Procedure:
The treated catalyst (I) (containing 0.3 g of metallic nickel) and 4.0 g of a 80% aqueous hydrazine hydrate solution were added dropwise to 300 g of an aqueous solution containing 23.0 g of 6-trifluoromethyl-2-quinoxalinol-4-oxide and 8 g of sodium hydroxide at 40° to 50° C., and the reaction was carried out at 40° to 80° C. for 5 hr. After the catalyst was removed by filtration, the filtrate was acidified to give 20.1 g (yield 94%) of 6-trifluoromethyl-2-quinoxalinol with melting point of 260° C.