Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:14]([C:15](=[O:26])[C:16]=1[O:17]C(=O)C1C=CC=CC=1)[CH2:13][CH:12]1[CH2:27][CH2:28][C:9]2([O:29][CH2:30][CH2:31][O:32]C(=O)C2C=CC=CC=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2].C([O-])C.[Na+]>C1COCC1.CCO.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:14]([C:15](=[O:26])[C:16]=1[OH:17])[CH2:13][CH:12]1[CH2:27][CH2:28][C:9]2([O:29][CH2:30][CH2:31][OH:32])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(OCCOC(=O)c2ccccc2)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(OCCO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
At room temperature, to a cold (ice-cooling) and stirred solution of 5-benzoyloxy-1-(2-benzoyloxy-ethoxy)-6-oxo-3,7-diazatricyclo[7.2.2.02,7]trideca-2,4-diene-4-carboxylic acid ethyl ester (330 mg, 0.604 mmol) in THF (6 mL) and EtOH (3.00 mL) was added 21% sodium ethanolate in EtOH (0.676 mL, 1.81 mmol) diluted with EtOH (3 mL) and the mixture stirred under N2 for 1 h. The mixture was diluted with ethyl acetate (10 mL) and extracted with water (10 mL×2). The aqueous extracts were acidified with 1N-HCl (3 mL) and extracted with ethyl acetate (10 mL×5). The ethyl acetate extracts were washed with brine, dried (Na2SO4) and concentrated to provide the title compound (130 mg, 0.38 mmol; 64% yield) as an oil: HPLC: retention time=1.33 min (area percent=95%); LCMS: m/z 339 (M+H); 1H NMR (500 MHz, CDCl3) δ ppm 1.43 (3H, t, J=7.2 Hz), 1.65 (2H, dt, J=12.3, 6.2 Hz), 1.85-1.97 (2H, m), 1.99-2.17 (4H, m), 2.46 (1H, brs), 3.60 (2H, t, J=4 Hz), 3.75 (2H, d, J=4.1 Hz), 4.06-4.15 (2H, m), 4.45 (2H, q, J=7.0 Hz), 10.48 (1H, brs); 13C NMR (126 MHz, CDCl3) δ ppm 14.0, 23.2, 27.6, 30.5, 53.9, 62.0, 63.2, 65.3, 76.7, 124.1, 148.2, 154.3, 159.7, 169.1.
Reaction SMILES: [N:1](=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:4](=O)[CH3:5])O.[CH3:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[N:23](Cl)=O.N=C=O>[Zn].C(O)(=O)C>[CH3:13][C:14]1[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:23][C:4]([CH3:5])=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:1]=1
Reactant: CCCCCCCC(C)=O
Reactant: O=NCl
Reactant: CCCCCCC(=NO)C(C)=O
Agent: N=C=O
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCCCc1nc(C)c(CCCCCC)nc1C

Procedure:
2,5-Dimethyl-3,6-dihexyl-pyrazine was prepared by first forming 3-oximino-2-nonanone by reacting 2-nonanone with nitrosyl chloride according to the method of BOUVEAULT (loc.cit.). The autocondensation of two moles of the imino-ketone in the presence of zinc and acetic acid [according to the method described in Chimia 11, 310 (1957)] yielded 2,5-dimethyl-3,6-dihexyl-pyrazine which had a b.p. of 112°-120° C./0.01 mm. Hg.
Reaction SMILES: [H-].[NH2:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][C:4]=1[C:15]#N.C[OH:18].O>C1(C)C=CC=CC=1.C1COCC1>[NH2:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][C:4]=1[CH:15]=[O:18]
Reactant: Cc1cc(-n2cncn2)cc(C#N)c1N
Reactant: CO
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(-n2cncn2)cc(C=O)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisobutylalumnium hydride (11.1 cm3 of a 1.5M solution in toluene) was added dropwise at 0° to a stirred suspension of 1-(4-amino-3-cyano-5-methylphenyl)-1,2,4-triazole (15 g) in THF (20 cm3). The solution was stirred at room temperature for 0.5 hours, heated under reflux for 2 hours, cooled, and treated with methanol (1 cm3) and water (100 cm3). Solid material was filtered off and washed with methanol (50 cm3) and the filtrate was evaporated in vacuo. The residue was taken into 2M hydrochloric acid (20 cm3), warmed for 10 minutes at 100° , and cooled. The solution was neutralised with saturated aqueous sodium carbonate solution and extracted with chloroform (4×50 cm3). The combined organic extracts were dried (MgSO4) and evaporated to give an oil which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate. Combination and evaporation of appropriate fractions followed by recrystallisation from ethyl acetate/hexan afforded the title compound, m.p. 209°-211° (1.27 g), characterised by n.m.r. and i.r. spectroscopy.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1.C1C[O:24][CH2:23][CH2:22]1>>[F:13][C:14]1[C:19]([C:23](=[O:24])[CH3:22])=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1
Reactant: C1CCOC1
Reactant: Fc1cccc(F)n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CC(=O)c1ccc(F)nc1F
Temperature: 25 °C

Procedure:
A solution of freshly distilled diisopropylamine (14.7 mL, 104.3 mmol) in 10 mL of anhydrous THF was cooled to −78° and treated with 1.6 M solution of n-BuLi in hexanes (64.0 mL, 102.5 mmol). The resulting solution naturally warmed to −20° and was maintained at −20° for 1.5 hours. The solution was cooled to −78° and 2,6 difluoro pyridine (37-1) was added dropwise. The reaction was continued with stirring for 2 hours at −78° C. before a solution of 9.7 mL (86.9 mmol) of the Weinryb amide was added in 20 mL of THF. The resulting solution was warmed to ambient temperature overnight before quenching with a brine solution. The mixture was extracted with EtOAc (3×), and the combined organic layers were washed with H2O (1×), brine (2×), dried over MgSO4, and concentrated in vacuo. The crude product was purified via flash silica gel chromatography (0-40% EtOAc/Hexane) to yield the desired product 37-2. 1H NMR (CDCl3): 2.68 (s, 3H), 6.95 (d, 1H), 8.50 (q, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:13])[CH:12]=1)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]2([CH3:17])[CH3:16])#[CH:2].[CH3:18][O:19][C:20](=[O:31])[C:21]([C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)([CH3:23])[CH3:22].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20](=[O:31])[C:21]([C:24]1[CH:25]=[CH:26][C:27]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([OH:13])[CH:12]=2)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]3([CH3:17])[CH3:16])=[CH:28][CH:29]=1)([CH3:23])[CH3:22]
Reactant: COC(=O)C(C)(C)c1ccc(I)cc1
Reactant: C#Cc1cc(O)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.057 g, 0.25 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent-2, 0.112 g, 0.37 mmol), triethyl amine (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230–400 mesh) and preparative normal phase HPLC using 5% ethyl acetate in hexane as the mobile phase, the title compound was obtained as a brown oil (0.035 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]2[C:19]3[C:20]4[CH:34]=[CH:33][S:32][C:21]=4[C:22](=[O:31])[NH:23][C:24]=3[C:25]([CH3:30])=[CH:26][C:27]=2[O:28]C)[CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][NH:6]C(=O)OC(C)(C)C.BrB(Br)Br>>[ClH:1].[NH2:6][CH2:5][CH2:4][C:3]1[CH:14]=[CH:15][C:16]([C:18]2[C:19]3[C:20]4[CH:34]=[CH:33][S:32][C:21]=4[C:22](=[O:31])[NH:23][C:24]=3[C:25]([CH3:30])=[CH:26][C:27]=2[OH:28])=[CH:17][C:2]=1[Cl:1]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(Cl)c1
Agent: BrB(Br)Br
Product: Cc1cc(O)c(-c2ccc(CCN)c(Cl)c2)c2c1[nH]c(=O)c1sccc12
Product: Cl
Yield: 102.8 %

Procedure:
Following General Procedure F, tert-butyl 2-chloro-4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethylcarbamate (120 mg, 0.24 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 1.45 mL, 1.45 mmol) to afford the desired product (52 mg, 57%) as a white solid: 1H NMR (500 MHz, MeOD) δ 7.64 (d, J=5.4 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.37 (d, J=1.4 Hz, 1H), 7.23 (dd, J=7.7, 1.4 Hz, 1H), 7.08 (s, 1H), 6.19 (d, J=5.4 Hz, 1H), 3.42-3.14 (m, 4H), 2.56 (s, 3H); ESI MS m/z 385 [C20H17ClN2O2S+H]+; HPLC 98.2% (AUC), tR=8.55 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].C1([O:20][C:21](=O)[NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([OH:33])[CH:31]=3)[CH:26]=[CH:25][CH:24]=2)C=CC=CC=1>CS(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:21]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([OH:33])[CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[O:20])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=C(Nc1cccc2ccc(O)cc12)Oc1ccccc1
Reactant: NCc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(C(F)(F)F)c1)Nc1cccc2ccc(O)cc12
Yield: 77.1 %

Procedure:
4-Chloro-3-trifluoromethyl-benzylamine (150 mg, 0.71 mmol) and (7-hydroxy-naphthalen-1-yl)-carbamic acid phenyl ester (200 mg, 0.7 mmol) were combined and stirred at ambient temperature in DMSO (3 mL) overnight. The product was purified by directly injecting the crude reaction onto a reverse phase prep-HPLC (90–10% water:acetonitrile gradient). The appropriate fractions were lyophilized to yield 1-(4-Chloro-3-trifluoromethyl-benzyl)-3-(7-hydroxy-naphthalen-1-yl)-urea (212.7 mg, 0.54 mmol). MS (MH+) 394.9; 1H NMR (CD3OD) δ 4.41 (s, 2H), 7.09 (dd, 1H, J=2.4 Hz), 7.21–7.26 (m, 2H), 7.46 (d, 1H, J=7.3 Hz), 7.54 (d, 2H, J=1.0 Hz), 7.62 (d, 1H, J=8.2 Hz), 7.71–7.75 (m, 2H). HPLC Rt=4.4 min (90–10% water:acetonitrile gradient, 100% pure).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C[N:14]([CH3:17])C=O.[C:18](Cl)(=O)[C:19](Cl)=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][Br:12])=[CH:7][C:3]=1[C:4]([NH:14][CH2:17][C:19]12[CH2:18][CH:10]3[CH2:9][CH:8]([CH2:7][CH:3]([CH2:2]3)[CH2:4]1)[CH2:11]2)=[O:6]
Reactant: O=C(O)c1cc(CBr)ccc1Br
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CBr)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-5-bromomethyl-benzoic acid (6.1 g) in dichloromethane (100 ml) at 0° C. were added dimethylformamide (0.2 ml) followed by oxalylchloride (3 ml). The reaction was stirred at room temperature for 0.5 hour and concentrated under vacuum. The acylchloride was redissolved in dichloromethane (100 ml) and and di-isopropylethylamine (6 ml) followed by adamantanemethylamine (3.5 ml) added at 0° C. The mixture was stirred at 0° C. for 10 min., then partitioned between diethyl ether and 1N aqueous hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by recrystallisation from dichloromethane/ethylacetate/i-hexane to afford the title compound as a white solid (6.5 g) (sample contained some of the corresponding benzyl chloride).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1.[CH3:24][O-:25].[Na+]>>[CH3:24][O:25][C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Reactant: C[O-]
Agent: [Na+]
Product: CCCOc1ccccc1-c1nc2nc(OC)nnc2c(=O)[nH]1

Procedure:
In a similar manner to Example 11, 3-methylthio-8-oxo-6-(2-propoxyphenyl)-7,8-dihydropyrimido[4,5-e][1,2,4]triazine (0.5 g) was treated for 3 hours with sodium methoxide (prepared from sodium, 0.17 g, and methanol) to afford the title compound, 0.34 g, m.p. 234°-235° C. (recrystallised from methanol).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH2:17]O)=[C:5]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[N:6]=1.S(Cl)(Cl)=[O:20].C([O:26][CH2:27][CH2:28][Cl:29])(=O)C.[H-].[Na+]>CN(C)C=O.O>[Cl:29][CH:28]([CH2:17][C:4]1[O:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)[C:27]([OH:20])=[O:26]
Reactant: CC(=O)OCCCl
Reactant: Cc1nc(-c2ccc3c(c2)CCCC3)c(CO)o1
Reactant: O=S(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc3c(c2)CCCC3)c(CC(Cl)C(=O)O)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a solution of [2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]methanol (3.3 g) in (40 mL) was added thionyl chloride (1.5 mL) at 0° C. After stirring at room temperature for 15 min, the reaction mixture was concentrated. To the residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil. To a mixed solution of 2-chloroethyl acetate (2.68 g) and N,N-dimethylformamide (40 mL) was added sodium hydride (60% in oil, 0.6 g) and the mixture was stirred at 0° C. for 5 min. To this the reaction mixture was added a solution of the aforementioned oil in N,N-dimethylformamide (10 mL) at room temperature and the mixture was stirred at room temperature for 2.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was diluted with ethanol (30 mL) and a 2N aqueous sodium hydroxide solution (16 mL) was added at 0° C. and the mixture was stirred for 20 min. Water was added to the reaction mixture and the mixture was washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 2-chloro-3-[2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]propionic acid (3.93 g, yield 91%) as colorless prism crystals. melting point: 141–142° C.
Reaction SMILES: [CH3:1][CH:2]([CH:25]([CH3:28])[CH2:26][CH3:27])[C:3]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:24])=[CH:11][N:12]3[C:19](=[O:20])[C:18]([C:21](O)=[O:22])=[CH:17][N:16]=[C:13]32)=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.ClC(OCC)=O.[C:42]1([CH:48]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[N:49]2[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][NH2:57])[CH2:51][CH2:50]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[C:58]1([CH:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:49]2[CH2:50][CH2:51][N:52]([CH2:55][CH2:56][NH:57][C:21]([C:18]3[C:19](=[O:20])[N:12]4[CH:11]=[C:10]([CH3:24])[C:9]5[C:14]([C:13]4=[N:16][CH:17]=3)=[CH:15][C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH:25]([CH3:28])[CH2:26][CH3:27])=[CH:7][CH:8]=5)=[O:22])[CH2:53][CH2:54]2)[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: CCC(C)C(C)C(=O)Nc1ccc2c(C)cn3c(=O)c(C(=O)O)cnc3c2c1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)C(C)C(=O)Nc1ccc2c(C)cn3c(=O)c(C(=O)NCCN4CCN(C(c5ccccc5)c5ccccc5)CC4)cnc3c2c1
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a stirred mixture containing 10-(2,3-dimethylpentanoylamino)-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylic acid (455 mg), triethylamine (0.174 ml) and dry dichloromethane (70 ml) was added slowly ethyl chloroformate (0.12 ml) at 0° C. under an inert atmosphere. After being stirred for 2 hours, a solution of 2-(4-diphenylmethyl-1-piperazinyl)-ethylamine (359 mg) in dry dichloromethane (10 ml) was added dropwise to the reaction mixture at 5° C. After stirring was continued for 12 hours at room temperature, the mixture was concentrated under reduced pressure. The residue was subjected to a column chromatography on silica gel with chloroform-methanol. The eluate was concentrated in vacuo to give residue, which was recrystallized from chloroform-ether to give N-[2-(4-diphenylmethylpiperazin-1-yl)ethyl]-7-methyl-10-(2,3-dimethylpentanoylamino)-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxamide (0.59 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:10]=1[CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[C:13]1[N:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][C:10]=1[CH2:11][N:12]([CH2:20][C:21]1[CH:22]=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[C:13]1[N:14]=[CH:15][C:16]([O:19][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:17][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)nc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[(2-Benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-ol (7.68 g) is dissolved in N,N-dimethylformamide (100 ml) and thereto are added ethyl 4-bromo-butyrate (2.3 ml) and potassium carbonate (2.22 g), and the mixture is stirred at room temperature overnight. To the reaction solution are added ethyl 4-bromo-butyrate (2.3 ml) and potassium carbonate (2.22 g), and the mixture is stirred at room temperature for 3 days. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give ethyl 4-{2-[(2-benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate as crude product (11.3 g). MS (m/z): 716 [M+H]+
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:15][C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:31][CH2:30][N:29]([C:4]([C:3]2[CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=[CH:10][C:2]=2[I:1])=[O:6])[CH2:28][CH2:27]1
Reactant: Fc1cc(C(F)(F)F)ccc1N1CCNCC1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3F)CC2)c1

Procedure:
Example CN was prepared in analogy to Example 123 from 2-Iodo-5-methanesulfonyl-benzoic acid (example BQ) and 1-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine (example H). MS (m/e): 574.2 (M+NH4+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:38]=[CH:37][O:36][N:35]=2)=[CH:30][CH:29]=1>CN(C)C=O>[O:36]1[CH:37]=[N:38][C:34]([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][N:11]([C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[CH2:18][OH:19])[S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])=[CH:29][CH:30]=2)=[N:35]1
Reactant: BrCc1ccc(-c2ncon2)cc1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCC[C@H]1CO
Reaction time: 2 h
Yield: 15.2 %

Procedure:
A suspension of 4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (300 mg, 1.0 mmol), cesium carbonate (390 mg, 1.2 mmol), and 3-(4-(bromomethyl)phenyl)-1,2,4-oxadiazole (280 mg, 1.2 mmol) in dimethylformamide (5 mL) was stirred for 2 h. The reaction was concentrated and purified by flash chromatography on a 40 g silica gel column using a gradient of 0 to 80% ethyl acetate in hexane, then by preparative HPLC to give N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (70 mg, 15%). 1H NMR (400 MHz, MeOD) δ ppm 9.23 (s, 1H), 8.00 (d, J=8.30 Hz, 2H), 7.75 (d, J=8.81 Hz, 2H), 7.54 (d, J=8.00 Hz, 2H), 7.51 (d, J=8.60 Hz, 2H), 4.55 (d, J=15.61 Hz, 1H), 4.36 (d, J=15.86 Hz, 1H), 3.52 (br. s., 1H), 3.31-3.38 (m, 1H), 3.14 (dd, J=11.08, 7.30 Hz, 1H), 1.87 (d, J=12.34 Hz, 1H), 1.53-1.75 (m, 2H), 1.30-1.53 (m, 3H), 0.98-1.22 (m, 3H). LC/MS R.T.=2.72 min; [M+H]+=462. HRMS [M+H]+ calc'd 462.1254, found 462.1241.
Reaction SMILES: C(OC(N1CCC2N(C)C3C(C(F)(F)F)=CC(NC4C=CC=CN=4)=CC=3C2C1)=O)(C)(C)C.C(OC([N:40]1[CH2:56][CH2:55][C@@H:43]2[N:44]([CH3:54])[C:45]3[C:46]([C:52]#[N:53])=[CH:47][C:48](Br)=[CH:49][C:50]=3[C@@H:42]2[CH2:41]1)=O)(C)(C)C.[Cl:57][C:58]1[N:63]=[CH:62][C:61]([NH2:64])=[CH:60][CH:59]=1.CC([O-])(C)C.[Na+]>>[Cl:57][C:58]1[N:63]=[CH:62][C:61]([NH:64][C:48]2[CH:49]=[C:50]3[C:45](=[C:46]([C:52]#[N:53])[CH:47]=2)[N:44]([CH3:54])[C@H:43]2[CH2:55][CH2:56][NH:40][CH2:41][C@@H:42]32)=[CH:60][CH:59]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: CC(C)(C)[O-]
Agent: CN1c2c(cc(Nc3ccccn3)cc2C(F)(F)F)C2CN(C(=O)OC(C)(C)C)CCC21
Agent: [Na+]
Product: CN1c2c(C#N)cc(Nc3ccc(Cl)nc3)cc2[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method A) as an oil (20 mg, 12%) from (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 196 mg, 0.5 mmol), 6-chloro-pyridin-3-ylamine(186 mg, 1.5 mmol) and NaOt-Bu (144 mg, 1.5 mmol). MS (ESI): 340 (base, M+H).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH3:17]>ClCCl>[Br:9][C:10]1[CH:15]=[C:14]([N+:7]([O-:8])=[O:6])[C:13]([F:16])=[CH:12][C:11]=1[CH3:17]
Reactant: Cc1cc(F)ccc1Br
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1cc(F)c([N+](=O)[O-])cc1Br

Procedure:
2.21 g (16.7 mmol) of nitronium tetrafluoroborate were suspended in 30 ml of dichloromethane. A solution of 3.0 g (15.9 mmol) of 2-bromo-5-fluorotoluene in 30 ml of dichloromethane was added dropwise under reflux. The mixture was then stirred under reflux for another 6 h. The mixture was then poured onto ice and extracted with dichloromethane, and the organic phase was washed with water, dried over sodium sulphate and concentrated on a rotary evaporator. This gave a yellow oil which formed crystals overnight. These were separated off, washed with 2 ml of pentane and dried. This gave 265 mg (6.9% of theory) of the title compound.