Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([N:52]2[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]2)=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
The solution of 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid (Aldrich) (21.88 g, 95.4 mmol), triethylamine (13.3 mL, 95.4 mmol) and HBTU [O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (Advanced Chem. Tech.)] (38.36 g, 101.0 mmol) in dry dimethylformamide (100 mL) was stirred at room temperature for five minutes before N-methyl-piperazine (10.6 mL, 95.5 mmol) was added. The pH of the reaction mixture was adjusted to 8 by the addition of triethylamine, the so obtained mixture was stirred at room temperature overnight, then concentrated in vacuo. The residue was treated with saturated sodium hydrogencarbonate solution (350 mL), extracted with ethyl acetate (3×250 mL), the combined organic layers were washed with saturated sodium hydrogencarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated. The residue was submitted to column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and chloroform:methanol=9:1 as eluent to yield 25.8 g (87%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13]Br)=[CH:8][CH:7]=1)=[O:4].[C-:23]#[N:24].[Na+].O>CS(C)=O>[F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:23]#[N:24])=[CH:8][CH:7]=1)=[O:4]
Reactant: [C-]#N
Reactant: O=C(Nc1ccc(CCBr)cc1)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reaction time: 18 h
Yield: 49.1 %

Procedure:
A solution of 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-bromoethyl)phenyl]butanamide (9.9 g), and sodium cyanide (1.72 g) in dimethylsulfoxide (50 mL) was stirred at room temperature under a nitrogen atmosphere for 24 hours. The mixture was treated with additional sodium cyanide (0.8 g) and the reaction was stirred for another 18 hours. The reaction mixture was poured into water (1 L) and extracted with diethyl ether. The extracts were washed with water and with saturated brine solution, dried over sodium sulfate, filtered and concentrated with a rotary evaporator. The crude orange residue was chromatographed on silica gel, eluted with a hexane-ethylacetate (7:3) mixture to give 4.2 g of 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-cyanoethyl)phenyl]butanamide as a yellow solid.
Reaction SMILES: Cl.C1C2C(COC([N:19]3[CH2:24][C@@H:23]([C:25](=[O:44])[N:26]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:32]=4)[CH:27]4[CH2:29][CH2:28]4)[CH2:22][C@@H:21]([NH2:45])[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:46](Cl)(=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48]>CC#N>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:26]([CH:27]2[CH2:28][CH2:29]2)[C:25]([C@H:23]2[CH2:22][C@@H:21]([NH:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:20][NH:19][CH2:24]2)=[O:44])=[CH:32][C:33]=1[O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1Cl
Agent: Cl
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)C(C)(C)C)C2)C2CC2)ccc1Cl

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-{[4-chloro-3-(3-methoxy-propoxy)-benzyl]-cyclopropyl-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride and pivaloyl chloride. MS: 480.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.29 min.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:15][N:16]([CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:27]=2)[CH:22]=[CH:21]1)[CH3:17]>C(O)(=O)C>[C:1]1([C:22]2[C:23]3[C:28](=[CH:27][C:26]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[N:20]([CH2:19][CH2:18][N:16]([CH3:17])[CH3:15])[CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCC1
Reactant: CN(C)CCn1ccc2ccc(-c3cccnc3)cc21
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCn1cc(C2=CCCCC2)c2ccc(-c3cccnc3)cc21
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
In a 20 mL vial equipped with a screw cap and a stir bar was added cyclohexanone (0.1 mL; 0.88 mmol), trifluoroacetic acid (1 mL) and acetic acid (0.75 mL). The mixture was heated at 110° C. under argon for 15 minutes. A solution of compound (a), above, (0.07 g; 0.25 mmol) in acetic acid (1 mL) was added. The resulting mixture was stirred for an additional 20 minutes at 110° C. The reaction mixture was quenched with potassium hydroxide (1N) (pH: 10; 80 mL) and extracted with ethyl acetate (30 mL). The organic phase was successively washed with water (3×30 mL), brine (30 mL), dried (sodium sulfate), filtered and solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using chloroform:methanol (95:5) to yield the title compound (0.6 g; 64%). 13C NMR (CDCl3): δ148.6, 147.8, 138.0, 137.3, 134.5, 131.5, 130.9, 125.9, 123.5, 122.5, 121.8, 118.9, 118.4. 107.8, 45.8, 44.8, 34.2, 28.6, 25.8, 23.2, 22.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][S:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[NH:11]2)=[CH:4][C:3]=1[O:26][CH3:27].Br[CH:29](Br)[CH3:30].C(N(CC)CC)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:30][CH2:29][N:11]3[CH:10]([CH2:15][S:14][CH2:13][CH:12]3[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH2:9]2)=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: COc1cc(NCC2CSCC(c3ccc(OC)c(OC)c3)N2)ccc1Cl
Reactant: CC(Br)Br
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1cc(N2CCN3C(CSCC3c3ccc(OC)c(OC)c3)C2)ccc1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 31.9 %

Procedure:
A solution of (4-chloro-3-methoxy-phenyl)-[5-(3,4-dimethoxy-phenyl)-thiomorpholin-3-ylmethyl]-amine (100 mg, 0.245 mmol, 1.0 equivalents), dibromoethane (0.31 ml, 3.55 mmol, 14.5 equivalents) and triethylamine (0.15 ml, 1.09 mmol, 4.5 equivalents) in dimethylacetamide (2 ml) was heated at 90° C. for 4 hours. Additional dibromoethane (0.16 ml, 1.84 mmol, 7.5 equivalents) and triethylamine (0.25 ml, 1.76 mmol, 7.2 equivalents) was added and reaction was stirred for 4 hours at 90° C. Additional dibromoethane (0.14 ml, 1.62 mmol, 6.6 equivalents) and triethylamine (0.10 ml, 0.71 mmol, 2.9 equivalents) were added and reaction was stirred 18 hours at 90° C. Reaction was cooled and filtered to remove triethylammonium hydrobromide. Filtrate was concentrated. Residue was purified on a 1000 micron preparative TLC. 34 mg of 8-(4-chloro-3-methoxy-phenyl)-4-(3,4-dimethoxy-phenyl)-octahydro-pyrazino[2,1-c][1,4]thiazine (Compound 8) was obtained, along with 36 mg recovered starting material. Yield of product: 32%. H1 NMR (400 MHz, CDCl3): 7.19 (1H, d), 6.86 (3H, m), 6.42 (2H, m), 3.89 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.50 (1H, m), 3.19 (2H, dd), 2.92 (1H, m), 2.75 (5H, m), 2.48 (2H, t), 2.15 (1H, dt). MS (LC-MS): Calculated for C22H27ClN2O3S 435.14, 435.24. IX. 2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine Via Scheme H
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([O-:9])=[O:8])=[CH:3][CH:2]=1.[Na+].O.Br[CH2:14][CH2:15][CH2:16][CH2:17][Sn:18]([CH3:21])([CH3:20])[CH3:19]>[Br-].C([P+](CCCC)(CCCC)CCCCCCCCCCCCCCCC)CCC.C1(C)C=CC=CC=1>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([CH2:14][CH2:15][CH2:16][CH2:17][Sn:18]([CH3:21])([CH3:20])[CH3:19])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: C[Sn](C)(C)CCCCBr
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)CCCC[Sn](C)(C)C)cc1
Yield: 37.7 %

Procedure:
Into a 125 ml single-necked round bottom flask fitted with a teflon coated magnetic stir bar and a reflux condenser was charged 4.45 g of sodium p-toluenesulfinate, 20 ml water, 10 ml toluene, 7 g of 75% 4-bromobutyltrimethylstannane and 0.44 g of tri-n-butylhexadecylphosphonium bromide. The mixture was refluxed for 2.5 hours with rapid stirring. On cooling, the organic phase was separated, dried over anhydrous magnesium sulfate and stripped of solvent on a rotary evaporator. The oil residue was distilled two times through a short path distillation head. The second distillation afforded 3.3 g of 4-(p-tolylsulfonyl)butyltrimethylstannane, b.p. 136°-140° C. (1×10-3 mm Hg). The presence of both the sulfonyl and trimethyltin moieties was indicated by strong infrared absorption bands at 1315 cm-1, 1300 cm-1, 1142 cm-1 (--SO2 --) and 765 cm-1 ([(CH3)3Sn--]. NMR spectroscopy showed the following:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22]1([CH:28]2[CH2:30][O:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[OH:29][CH:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:30][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: c1ccc(C2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)c3ccccc3)CC1)O2

Procedure:
Compound 167 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-phenyloxirane and conditions outlined in procedure X. M.p.=193-195° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.09-7.75 (m, 3H), 7.6-7.5 (m, 1H), 7.4-7.2 (m, 5H), 5.03 (br. s, 1H), 4.93 (br. s, 1H), 3.07 (s, 2H), 2.9-2.78 (m, 2H), 2.65-2.45 (m, 4H), 2.05-1.7 (m, 4H); LCMS: 422 [M+H].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.CO.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C[O-].[Na+]>O>[C:15]1([C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 12 L round-bottomed flask was equipped with a reflux condenser and a mechanical stirrer, and the system was purged with nitrogen gas. 6-indole carboxylic acid (300.00 g, 1.86 mole, 3 equivalents) was charged into the flask, followed by MeOH (5.5 L). After stirring for 10 min at room temperature, cyclohexanone (579 mL, 5.58 mole) was added. Methanolic sodium methoxide (25% w/w, 2.6 L, 11.37 mole, 6.1 equivalents) was added in portions over 10 min. The mixture was then refluxed for 48 h. After cooling to room temperature, water (4 L) was added and methanol removed under reduced pressure. The residual aqueous phase was acidified to pH 1 with concentrated HCl (˜1.2 L). The resulting yellowish precipitate was collected by filtration, washed with water and dried under vacuum at 50° C. The desired cyclohexene derivative was obtained as a beige solid (451.0 g, 100% yield).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1.O1CCCC1>CCOCC>[OH:9][C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1
Reactant: Br[Mg]c1ccccc1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)[C@@H]1CC(O)(c2ccccc2)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Phenylmagnesium bromide in ether (3.00M, 0.400 mL) was added to a solution of 1-tert-butyl 2-methyl(2S)-4-oxopyrrolidine-1,2-dicarboxylate (243.0 mg, 0.0009989 mol) in tetrahydrofuran (5.00 mL, 0.0616 mol) at −40° C. The reaction mixture was stirred at between −40° C. and −10° C. for 2 h and then was quenched with amonium chloride solution (5 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16]C3C=NC=CC=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.Br[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2cc(F)cc(F)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a light yellow solid, MS (ISP): m/e=344.0 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:17]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[S:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=1)(=[O:19])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: O=C(O)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
Prepared as in example 5-27 from dibenzylamine and methyl 4-(chlorosulfonyl)-benzoate (Example 5-10c). MS (M−H, 380.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 4.52 (s, 4H), 7.10 (m, 4H), 7.25 (m, 6H), 8.00 (d, 2H, J=8.4 Hz), 8.15 (d, 2H J=8.4 Hz), 13.5(s, broad, 1H).
Reaction SMILES: [Cl-].[Eu+3].[Cl-].[Cl-].[Na+].[NH2:6][C@H:7]([C:27]([O-:29])=[O:28])[CH2:8][C:9]1[CH:16]=[C:14]([I:15])[C:13]([O:17][C:18]2[CH:25]=[C:23]([I:24])[C:22]([OH:26])=[C:20]([I:21])[CH:19]=2)=[C:11]([I:12])[CH:10]=1>CN(C)C=O.C(O)C>[NH2:6][C@H:7]([C:27]([OH:29])=[O:28])[CH2:8][C:9]1[CH:10]=[C:11]([I:12])[C:13]([O:17][C:18]2[CH:19]=[C:20]([I:21])[C:22]([OH:26])=[C:23]([I:24])[CH:25]=2)=[C:14]([I:15])[CH:16]=1
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)[O-]
Agent: [Cl-]
Agent: [Eu+3]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O

Procedure:
Fluorescent compound (v) synthesized in Example 4 was dissolved in dimethylformamide at a concentration of 5.0×10-5M, and thyroxine sodium salt was dissolved in ethanol at a concentration of 5.0×10-5M. The fluorescent compound (v) solution (100 μl) and the thyroxine sodium salt solution (100 μl) of ethanol were mixed and incubated for 30 minutes at room temperature with stirring. The resulting solution was subjected to a HPLC purification (column: AP-313, YMC Co., solvent: methanol: water=3:7(v:v) including 0.02% acetic acid) and the fluorescent compound (v)-labelled thyroxine was purified. The fluorescent compound (v)-labelled thyroxine was identified by measuring the thyroxine activity using an enzyme immunoassay (Boehringer Mannheim GmbH), and by measuring fluorescence intensity of the solution prepared by mixing equal volume of europium chloride (1×10-5M) and the fraction.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:19]=1[N:18]=[C:9]([C:10]([NH:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1)=[O:11])[CH:8]=[C:7]2[O:20][CH3:21].COC1C2C(=C([N+]([O-])=O)C=CC=2)N=C(C([NH:29]C2NN=NN=2)=O)C=1>>[NH2:29][C:4]1[CH:5]=[C:6]2[C:19](=[CH:2][CH:3]=1)[N:18]=[C:9]([C:10]([NH:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1)=[O:11])[CH:8]=[C:7]2[O:20][CH3:21]
Reactant: COc1cc(C(=O)Nc2nnn[nH]2)nc2c(N)cccc12
Reactant: COc1cc(C(=O)Nc2nnn[nH]2)nc2c([N+](=O)[O-])cccc12
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc2ccc(N)cc12

Procedure:
8-Amino-4-methoxy-N(1H-tetrazol-5-yl)quinaldamide, m.p. 276° (d), was prepared by the hydrogenation of 4-methoxy-8-nitro-N(1H-tetrazol-5-yl)quinaldamide.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=5)[S:20][C:13]=34)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:27]([OH:29])=O.[NH2:30][CH2:31][CH2:32][CH2:33][OH:34].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:34][CH2:33][CH2:32][CH2:31][NH:30][C:27]([C:3]1[C:4]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=5)[S:20][C:13]=34)=[CH:7][C:5]=2[S:6][C:2]=1[CH3:1])=[O:29]
Reactant: Cc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)O
Reactant: NCCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)NCCCO
Yield: 59.6 %

Procedure:
This material was prepared by the reaction of 2-methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}benzo[b]thiophene-3-carboxylic acid 117b (85 mg, 0.20 mmole) with 3-amino-1-propanol (46 μL, 0.44 mmole), N,N-diisopropylethylamine (77 μL, 0.30 mmole), and HBTU (115 mg, 0.303 mmole) in a manner as previously described for example 117. The crude material was purified by silica gel chromatography (10:30:60% MeOH/CH2Cl2/EtOAc) to give a yellow solid (57 mg, 59%). 1H NMR (DMSO-d6, 300 MHz) δ8.52 (1H, d, J=5.27 Hz), 8.37 (1H, t, J=5.56 Hz), 7.95 (1H, d, J=2.26 Hz), 7.88 (1H, s), 7.82 (1H, d, J=8.85 Hz), 7.40 (1H, s), 7.33 (1H, dd, J=2.35, 8.76 Hz), 7.02 (1H, d, J=0.94 Hz), 6.70 (1H, d, J=5.46 Hz), 4.51 (1H, t, J=5.09 Hz), 3.98 (3H, s), 3.50 (2H, q, J=6.22 Hz), 3.35 (2H, m), 2.60 (3H, s), 1.71 (2H, m).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([CH3:27])[CH2:26][O:25][CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([N:23]3[C:22]([CH3:27])([CH3:21])[CH2:26][O:25][CH2:24]3)=[O:20])=[N:8][C:9]=2[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: CC1(C)COCN1
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COCN1C(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5 g)) was reacted with 4,4-dimethyloxazolidine (CAN 51200-87-4) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=355.5 [MH+].
Reaction SMILES: [C:1]1([C:7]2[CH:22]=[CH:21][C:10]([CH:11](CO)[O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[CH:9][C:8]=2[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24](O)C>[C].[Pd]>[CH2:1]([C:7]1[CH:22]=[CH:21][C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:9][C:8]=1[CH3:23])[C:6]1[CH:24]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: Cc1cc(C(CO)OC2CCCCO2)ccc1-c1ccccc1
Reactant: CCO
Agent: [Pd]
Product: Cc1cc(COC2CCCCO2)ccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
2-(4-Phenylhydroxymethyl-3-methylbenzyloxy)tetrahydropyran (2.5 g, 8 millimol) was dissolved in ethanol (20 ml). 5%-palladium carbon was added at a catalytic amount, and stirred at room temperature under hydrogen atmosphere for 6 days. After the insoluble material was distilled away, the filtrate was concentrated, and the residue was separated and purified by using a silica-gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (1.65 g, 5.6 millimol).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:25]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>>[O:31]=[S:25]1(=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Reactant: O=S1(=O)CCCCN1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3)CC2)nc1C
Yield: 81.7 %

Procedure:
Using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (218 mg) described in Preparation Example 120 and [1,2]thiazinane 1,1-dioxide (68 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (181 mg) was obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][N:9]1[CH2:25][CH2:24][C:12]2[N:13]([CH:21]=[CH:22][CH3:23])[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=3[C:11]=2[CH2:10]1.O>N(CCO)(CCO)CCO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][N:9]1[CH2:25][CH2:24][C:12]2[N:13](/[C:21](/[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:22]\[CH3:23])[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=3[C:11]=2[CH2:10]1
Reactant: Ic1ccccc1
Reactant: CC=Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: OCCN(CCO)CCO
Solvent: O
Product: C/C=C(/c1ccccc1)n1c2c(c3cc(C)ccc31)CN(C)CC2
Temperature: 100 °C
Reaction time: 14 h
Yield: 39.5 %

Procedure:
Iodo benzene (0.5 g, 2.4 mmol) and 2,8-dimethyl-5-(prop-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (588 mg, 2.4 mmol) were charged in triethanolamine (4 mL). Palladium (II)acetate (5 mg, 0.024 mmol) was added and stirred at 100° C. for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added. The desired compound was extracted with diethyl ether twice. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford 0.3 g of product. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.24 (s, 1H), 7.18 (m, 3H), 6.96-6.82 (m, 4H), 6.62 (m, 1H), 4.66 (m, 1H), 4.30 (m, 1H), 3.64 (m, 1H), 3.42 (m, 1H), 3.0 (s, 1H), 2.80 (m, 1H), 2.60 (m, 1H), 2.36 (s, 3H), 1.50 (d, 3H).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.C(N(CC)CC)C.Cl.Cl.[N:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:27]CC(N)[CH2:24][CH2:23]1>C(Cl)Cl>[N:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:27][CH2:10][CH:9]([NH:8][C:6]([N:3]2[CH:2]=[CH:1][N:5]=[CH:4]2)=[O:7])[CH2:24][CH2:23]1
Reactant: NC1CCN(c2ccccn2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A suspension comprising CDI (2.29 g, 14 mmol) and triethylamine (3.8 ml, 27 mmol) in dry DCM (20 ml) is treated portionwise over 5 minutes with 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylamine dihydrochloride (prepared using the procedure described in international patent application WO 01/94368) (2.88 g, 13 mmol). The reaction mixture is stirred at room temperature for 4.5 hours to yield the title compound as a 0.43 M solution in DCM.