Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].Cl>O.C(OCC)(=O)C.CN(C)C=O>[F:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:22]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 74.5 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 200 ml were charged 6.51 g (47.2 mmol) of potassium carbonate, 20 ml of N,N-dimethylformamide, 6.24 g (46.7 mmol) of dimethyl malonate with a purity of 99% and 5.00 g (30.8 mmol) of 2,4-difluoronitrobenzene with a purity of 98% under argon atmosphere, and under stirring, the mixture was reacted at room temperature for one hour and further by raising to 70° C. for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, 100 ml of ethyl acetate was added to the mixture, and 10.5 ml (62.8 mmol) of 6 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, after adding 50 ml of water to the reaction mixture, the organic layer was separated, and washed successively with 20 ml of water and 20 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler:Daisogel 1002W, eluent:hexane:ethyl acetate=9:1 (volume ratio)) to obtain 6.22 g (isolation yield: 73%) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate as white crystals with a purity of 98% (areal percentage by high performance liquid chromatography).
Reaction SMILES: C1(=O)NC(=O)C2=CC=CC=C12.[K].[OH:13][C@H:14]1[CH2:49][C@@H:48]2[C@:35]([CH3:52])([CH2:36][CH2:37][C@H:38]3[C@H:47]2[CH2:46][CH:45]=[C:44]2[C@:39]3([CH3:51])[CH2:40][CH2:41][C@H:42]([OH:50])[CH2:43]2)[C@H:15]1[C@H:16]([CH3:34])[CH2:17][CH2:18][CH2:19][C@@H:20]([CH3:33])[CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32]>>[O:13]=[C:14]1[CH2:49][C@@H:48]2[C@:35]([CH3:52])([CH2:36][CH2:37][C@H:38]3[C@H:47]2[CH2:46][CH:45]=[C:44]2[C@:39]3([CH3:51])[CH2:40][CH2:41][C@H:42]([OH:50])[CH2:43]2)[C@H:15]1[C@H:16]([CH3:34])[CH2:17][CH2:18][CH2:19][C@@H:20]([CH3:33])[CH2:21][N:22]1[C:23](=[O:32])[C:24]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]2[C:26]1=[O:27]
Reactant: C[C@H](CCC[C@@H](C)[C@H]1[C@@H](O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CN1C(=O)c2ccccc2C1=O
Agent: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: C[C@H](CCC[C@@H](C)[C@H]1C(=O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CN1C(=O)c2ccccc2C1=O

Procedure:
According to Scheme 1, (25R)-16β-26-dihydroxycholesterol (2), prepared in one step from diosgenin, is selectively reacted at the C-26 hydroxyl group with p-toluene sulfonyl chloride to yield (25R)-16β-26-dihydroxycholesterol 26-tosylate (3) which is then reacted with potassium phthalimide. The resulting (25R)-16β-hydroxy-26-phthalimidocholesterol (4) is then subjected to a modified Jones oxidation which selectively oxidizes the 16β hydroxy group to form (25R)-16-oxo-26-phthalimidocholesterol (5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[N+:32]([C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[C:37](=[O:49])[N:38]([CH2:45][C:46](O)=[O:47])[C:39]2=[O:44])([O-:34])=[O:33]>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:46](=[O:47])[CH2:45][N:38]1[C:37](=[O:49])[C:36]2[C:40](=[CH:41][CH:42]=[CH:43][C:35]=2[N+:32]([O-:34])=[O:33])[C:39]1=[O:44]
Reactant: O=C(O)CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (100 mg, 0.238 mmol) was placed in a 50 ml round bottom flask and dissolved in DMF (3 ml); EDC (45.6 mg, 0.238 mmol) was added to it followed by DMAP (29.1 mg, 0.238 mmol) and 2-(4-nitro-1,3-dioxoisoindolin-2-yl)acetic acid (90 mg, 0.357 mmol). The reaction was stirred at RT for 6 hours. The reaction was quenched by adding 30 ml of HCl/H2O (1M) and extracted with EtOAc (30 ml). The organic phase (EtOAc) was extracted with HCl/H2O 1M (30 ml; ×3) and subsequently with K2CO3/H2O (20 ml; ×3). The resulting organic extract was dried over Na2SO4, filtered and the solvent removed under reduced pressure to yield 120 mg of title compound (77% yield). 1H NMR (400 MHz, acetone) δ. ppm 8.35 (d, J=7.50 Hz, 1H), 8.24-8.30 (m, 1H), 8.16-8.24 (m, 3H), 7.16-7.25 (m, 2H), 7.05 (dd, J=8.16, 1.98 Hz, 1H), 6.94 (t, 1H, CHF2), 6.14 (dd, J=9.48, 4.63 Hz, 1H), 4.52 (s, 2H), 4.01 (dd, J=6.62, 3.97 Hz, 2H), 3.54 (dd, J=14.33, 9.48 Hz, 1H), 3.26-3.40 (m, 1H), 1.25-1.38 (m, 1H), 0.56-0.73 (m, 2H), 0.36-0.48 (m, 2H); MS/ESI+ 652.1 [MH]+
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:23][O:24][CH2:25][CH:26]([C:34]1[CH:35]=[CH:36][C:37]([CH:40]=[O:41])=[N:38][CH:39]=1)[O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1.C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH3:23][O:24][CH2:25][CH:26]([C:34]1[CH:35]=[CH:36][C:37]([C:40](=[O:41])[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:38][CH:39]=1)[O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1
Reactant: COCC(OC1CCCCO1)c1ccc(C=O)nc1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(OC1CCCCO1)c1ccc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)nc1
Yield: 53.8 %

Procedure:
A mixture of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.07 g), 5-[2-methoxy-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyridine-2-carbaldehyde (0.97 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (90 mg), triethylamine (0.23 mL), tetrahydrofuran (8 mL) and ethanol (8 mL) was stirred with heating under reflux for 1 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (1.05 g, yield 54%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 588 (MH+).
Reaction SMILES: O[NH-].C1[CH2:7][O:6][CH2:5][CH2:4]1.C(#[N:10])C.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:24]1([P:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1.[O:6]1[CH2:5][CH2:4][N:10]=[CH:7]1
Reactant: CC#N
Reactant: C1CCOC1
Agent: [NH-]O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C1=NCCO1

Procedure:
Hydroxyamide IX is then subjected to cyclodehydration in an inert organic solvent (e.g., THF, acetonitrile or methylene chloride) under an inert atmosphere (e.g., argon) with triphenylphosphine (employing a molar ratio of IX:triphenylphosphine of about 0.5:1 to about 1:1) and carbon tetrachloride in the presence of an amine base (e.g., triethylamine or diisopropylethylamine) to form an oxazoline ##STR26##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1>C1COCC1.C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(COc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(COc2ccc(N)cc2)cc1

Procedure:
The above nitro compound was hydrogenated in THF-ethanol in the presence of Raney nickel catalyst, providing 4-[(4-methoxyphenyl)methoxy]benzenamine, mp 118°-120° C.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[O:21][CH:20]=[N:19][C:18]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1[C:28](=O)[N:27](Br)[C:25](=O)C1>C(Cl)Cl>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[O:21][C:20]([N:27]([CH3:28])[CH3:25])=[N:19][C:18]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3ocnc3C)c(C)nc12
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3oc(N(C)C)nc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.7 %

Procedure:
230 mg of 8-(1-Ethyl-propyl)-2,6-dimethyl-3-(4-methyl-oxazol-5-yl)-imidazo[1,2-b]pyridazine (0.77 mmol) is dissolved in 20 ml of CH2Cl2 and 178 mg of NBS (1.0 mmol) is added. The reaction mixture is stirred at room temperature overnight. The reaction mixture is washed with sat. Na2S2O3, sat. NaCl, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1) to give 36 mg of the title compound. Yield 12%. mass spectrum (m/e): 378 (M+1). 1H-NMR (CDCl3): 6.82 (s, 1H), 3.39 (m, 1H), 2.58 (s, 3H), 2.53 (s, 3H), 2.26 (s, 3H), 1.85 (m, 1H), 0.89 (t, J=7.4 Hz, 6H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([O:17][C:18]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=O)C(=O)C1.CO.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>O>[OH:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][C:18]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:17])=[CH:27][CH:26]=1
Reactant: O=C(CCc1ccc(O)cc1)ON1C(=O)CCC1=O
Reactant: NCCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(CCc1ccc(O)cc1)NCCc1ccccc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
β-Phenylethylamine is derivatized with Bolton-Hunter reagent as follows. β-Phenylethylamine and Bolton-Hunter reagent were mixed in equimolar quantities in a 1:1 solution of methanol and sodium phosphate buffer (1M, pH 8). After 30 minutes, an excess of water was added. A crystalline solid was collected, washed with water and dried in vacuo giving 1-[3-(4-hydroxyphenyl)-propionylamino]-2-(phenyl) ethane in 75% yield.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][C:11]2=O)(=[NH:5])[NH2:4].Cl.[NH2:18][N:19]1[CH2:23][CH2:22][N:21]=[C:20]1[NH2:24]>C(O)(C)C>[ClH:1].[ClH:1].[C:3]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][C:11]2=[N:18][N:19]1[CH2:23][CH2:22][N:21]=[C:20]1[NH2:24])(=[NH:5])[NH2:4]
Reactant: N=C(N)c1cccc2c1CCCC2=O
Reactant: NC1=NCCN1N
Agent: Cl
Solvent: CC(C)O
Product: N=C(N)c1cccc2c1CCCC2=NN1CCN=C1N
Reaction time: 16 h

Procedure:
0.2 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) is added, with stirring, to a solution of 0.25 g (0.001 mol) of 5-(amidino)-1-tetralone hydrochloride and 0.136 g (0.001 mol) of 1,2-diamino-4,5-dihydro-imidazole hydrochloride in 5 ml of iso-propanol, and the mixture is stirred at 80°-90° C. for 16 hours. The reaction mixture is filtered while hot and the filtration product is washed with isopropanol and dried, yielding the title compound, m.p. >220° C. (decomp.), 1H-NMR (DMSO/D2O): δ=8.15 (d, 1H); 7.67 (d, 1H); 7.55 (t, 1H); 4.17 (t, 2H); 3.68 (t, 2H); 3.23 (m, 2H); 3.15 (m, 2H); 1.9 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[CH:15]=2)[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)=[N:21][CH:22]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([NH:12][C:9]3[CH:10]=[CH:11][C:6]4[N:7]([CH:15]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)=[O:30])=[CH:25][CH:24]=2)=[N:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccc2nc(C3CC3)cn2c1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cn2)cc1
Product: O=C(Nc1ccc2nc(C3CC3)cn2c1)c1ccc(-c2ccc(Cl)cn2)cc1

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-6-nitroimidazo[1,2-a]pyridine and 4-(5-chloro-2-pyridyl)benzenecarboxylic acid, to provide 4-(5-chloro-2-pyridyl)-N-(2-cyclopropylimidazo[1,2-a]pyridine-6-yl)benzamide as white solid. Further treating the resulting compound in the manner similar to Example 36, the title compound was obtained as white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17]I.OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C>[CH3:17][O:11][C:10](=[O:12])[C:9]1[CH:13]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=[CH:7][C:8]=1[NH2:14]
Reactant: CC(C)Oc1ccc(N)c(C(=O)O)c1
Reactant: CI
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC(C)C)ccc1N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 13.2 %

Procedure:
To a solution of 5-isopropoxy-2-amino-benzoic acid (806 mg) in DMF (10 mL) was added 60% in oil NaH (182 mg, 4.53 mmol) at 0-5° C. under an argon atmosphere. The ice bath was removed and the mixture was stirred for 40 min at room temperature. After addition of methyl iodide (0.33 mL, 5.45 mmol) the mixture was stirred at room temperature for an additional 6 h. 10% KHSO4/Na2SO4 was added and the mixture was extracted, washed with brine, dried (Na2SO4), and concentrated to dryness. Purification by chromatography gave 114 mg of 5-isopropoxy-2-amino-benzoic acid methyl ester.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([N+:18]([O-])=O)[CH:15]=[CH:16][CH:17]=1>Cl.[Fe]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[NH2:18]
Reactant: O=[N+]([O-])c1cccc(OCc2nc3ccccc3s2)c1
Agent: [Fe]
Agent: Cl
Product: Nc1cccc(OCc2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a suspension of 3-[(2-benzthiazolyl)methoxy]nitrobenzene (18.6 g) in ethanolic hydrochloric acid is added powdered iron. The reaction is stirred overnight at room temperature. After neutralization with saturated aqueous sodium bicarbonate, the mixture is extracted with methylene chloride (3X). The extract is dried over magnesium sulfate and concentrated to give 15.1 g (90% yield) of product. m.p. 117°-120° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23])=[CH:18][C:17]=1[C:29]([F:32])([F:31])[F:30]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:22](=[O:23])[CH:21]([O:20][C:19]1[CH:27]=[CH:28][C:16]([Cl:15])=[C:17]([C:29]([F:31])([F:32])[F:30])[CH:18]=1)[CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Oc1ccc(Cl)c(C(F)(F)F)c1)C(=O)Cl
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC(Oc1ccc(Cl)c(C(F)(F)F)c1)C(=O)NCc1ccccc1
Yield: 43 %

Procedure:
In 50 ml of toluene were dissolved 1.6 g (0.015 mole) of benzylamine and 2.4 g (0.030 mole) of pyridine. Then, was added dropwise thereto a solution of 3.0 g (0.010 mole) of 2-(4-chloro-3-trifluoromethylphenoxy)-butyroyl chloride in 30 ml of toluene and the mixture was treated, according to the same procedure as in Synthesis Example 10. The resultant crude crystals were recrystallized from ethanol to give 1.6 g of N-benzyl-2-(4-chloro-3-trifluoromethylphenoxy)-butyramide melting at 93°-95° C. as colorless needless.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.[OH-].[NH4+].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>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc2cc(-c3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Yield: 91.1 %

Procedure:
A mixture of 1-benzenesulfonyl-5-bromo-2-methyl-1H-indole (810 mg, 2.31 mmol), phenylboronic acid (850 mg, 6.97 mmol) and tetrakis(triphenylphosphine)palladium(0) (55 mg, 0.029 mmol) in 20 mL of toluene, 10 mL of ethanol, and 5 mL of 2 M sodium carbonate was warmed at reflux for 4 hours. The reaction was monitored by TLC (ethyl acetate-hexanes (5:95), 2× developed; and toluene-hexanes (1:1)) indicating a slightly more polar product. The mixture was cooled and diluted with 12% aqueous ammonium hydroxide solution and extracted with three 15 mL portions of ethyl acetate. The combined organic layers were washed with three 15 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture was adsorbed onto silica gel and chromatographed on silica gel using ethyl acetate-hexanes (1:99, then 2:98, then 3:97) to afford 731 mg (91% yield) of 1-benzenesulfonyl-2-methyl-5-phenyl-1H-indole.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:16][N:17]([CH2:25][CH:26]=O)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C([BH3-])#N.[Na+]>CO.C(O)(=O)C.CO.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:15])[C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:5][N:6]([CH2:26][CH2:25][N:17]([CH3:16])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:7][CH2:8]1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: CN(C)C1(c2ccccc2)CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CN(CCN1CCC(c2ccccc2)(N(C)C)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
7 g (1 equiv.) of N,N-dimethyl-4-phenylpiperidine-4-amine were added in portions to a solution of 6.5 g (1.5 equiv.) of tert-butyl methyl(2-oxoethyl)carbamate in 60 ml of methanol. The reaction mixture was cooled to 0° C., 3.97 g (2.5 equiv.) of sodium cyanoborohydride were added in portions, and stirring was then carried out for 10 minutes at room temperature. The resulting reaction mixture was adjusted to a pH of ˜5 by means of acetic acid and was stirred for 12 hours at room temperature. The progress of the reaction was monitored by means of thin-layer chromatography (20% MeOH/CHCl3). Because the reaction was not yet complete, 1.5 g of sodium cyanoborohydride and acetic acid were added and the reaction mixture was stirred for a further 35-40 minutes.
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:12][C:13]([OH:15])=O)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:18]([O:20][C:21]([C@H:23]1[C@@H:28]([NH:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C@H:27]2[CH2:35][C@@H:24]1[CH2:25][CH2:26]2)=[O:22])[CH3:19].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:18]([O:20][C:21]([C@H:23]1[C@@H:28]([N:29]([C:13](=[O:15])[CH2:12][C:7]2[NH:6][C:5]3[CH:16]=[CH:17][C:2]([I:1])=[CH:3][C:4]=3[S:9](=[O:10])(=[O:11])[N:8]=2)[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C@H:27]2[CH2:35][C@@H:24]1[CH2:25][CH2:26]2)=[O:22])[CH3:19]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC(C)C
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in US patent application US 2008/0031852, 0.2 g, 0.546 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). (1S,2R,3S,4R)-3-(3-Methyl-butylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 22a, 0.138 g, 0.546 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g, 0.573 mmol). Then N-methylmorpholine (0.116 g, 1.15 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 16 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-[[2-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a light yellow oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C24H32IN3O5S 601.11, found 602.6 [M+H+].
Reaction SMILES: [CH3:1][C:2]([CH3:9])([C:6](Cl)=[O:7])[C:3](Cl)=[O:4].CN(C)C(=O)C.Cl.[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([NH:31][CH3:32])[C:28]([NH2:33])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[NH:33][C:6](=[O:7])[C:2]([CH3:9])([CH3:1])[C:3](=[O:4])[N:31]([CH3:32])[C:29]=2[CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Reactant: CNc1cc(OCc2ccccc2)ccc1N
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(C)(C)C(=O)Nc2ccc(OCc3ccccc3)cc21
Reaction time: 2.5 h
Yield: 83 %

Procedure:
Under ice cooling, dimethylmalonic acid dichloride (9.9 mL, 74.9 mmol) was added dropwise to a N,N-dimethyl acetamide (90 mL) solution of 5-benzyloxy-N1-methylbenzene-1,2-diamine hydrochloride (18.0 g, 68.0 mmol). The mixture was stirred at the same temperature for 2.5 hours, and water (90 mL) was added thereto. The reaction solution was stirred at 10° C. or less for 30 minutes, and precipitated crystals were collected by filtration. The resulting crystals were washed with water, then added to methanol (180 mL), and heated under reflux. The mixture was cooled and stirred at 10° C. or less for 30 minutes, and precipitated crystals were collected by filtration. The resulting crystals were washed with methanol (36 mL), and dried at 60° C., thereby obtaining 18.3 g of a white, powdery target compound (yield: 83%).