Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].[CH2:22]([N:24]([CH2:32][CH2:33][CH2:34]Cl)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23]>CN(C)C=O>[CH2:22]([N:24]([CH2:32][CH2:33][CH2:34][N:7]1[C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[N:10]([CH3:13])[C:11](=[O:12])[C:5]2[C:4]([CH3:19])=[CH:3][C:2]([CH3:1])=[N:18][C:6]1=2)[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH3:23]
Reactant: Cc1cc(C)c2c(n1)Nc1ccccc1N(C)C2=O
Reactant: CCN(CCCCl)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CCCN1c2ccccc2N(C)C(=O)c2c(C)cc(C)nc21)Cc1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture consisting of 12.3 gm of 6,11-dihydro-2,4,6-trimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 120 ml of dimethyl formamide and 3.05 gm of 50% sodium hydride in mineral oil was stirred at 60° C. for 2 hours. Thereafter, 17 gm of 3-(N-ethyl-N-benzyl-amino)-propyl chloride were added dropwise, and the solution was stirred at 120° C. for 2 hours. After evaporating the solution in vacuo, the residue was distilled, yielding 68% of theory of 11-[3-(N-ethyl-N-benzyl-amino)-propyl]-6,11-dihydro-2,4,6-trimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one having a b.p. of 236°-238° C. at 0.3 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][CH2:13][CH3:14])=[CH:9][N:10]=2)[N:7]=1.[O:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][NH2:24])[CH2:17][CH2:16]1.Cl>CCOCC>[ClH:1].[CH2:13]([O:12][CH2:11][C:8]1[N:6]2[N:7]=[C:2]([NH:24][CH2:23][CH2:22][CH2:21][N:18]3[CH2:19][CH2:20][O:15][CH2:16][CH2:17]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:14]
Reactant: CCOCc1cnc2ccc(Cl)nn12
Reactant: NCCCN1CCOCC1
Agent: Cl
Solvent: CCOCC
Product: CCOCc1cnc2ccc(NCCCN3CCOCC3)nn12
Yield: 17 %

Procedure:
Prepared from 6-chloro-3-(ethoxymethyl)imidazo[1,2-b]pyridazine (8b) and 3-morpholinopropylamine according to general procedure 4 (step B). The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (36 mg, 17%) as a white solid; 1H NMR (500 MHz, CD3OD) δ 7.64 (d, J=9.7 Hz, 1H), 7.50 (s, 1H), 6.77 (d, J=9.7 Hz, 1H), 4.80 (s, 2H), 3.90-3.88 (m, 4H), 3.60 (q, J=7.1 Hz, 2H), 3.50 (t, J=6.4 Hz, 2H), 3.26-3.18 (m, 6H), 2.17-2.11 (m, 2H), 1.20 (t, J=7.0 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 155.6, 137.5, 130.0, 127.0, 125.3, 115.5, 66.7, 65.5, 61.4, 57.0, 53.5, 39.7, 24.6,15.5; HPLC tR=7.7 min (Luna), 97.6%; ES-MS: (M+H)=320 m/z.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]=[C:10]=[O:11])[CH:3]=1.[Br:12][C:13]1[C:22]2[CH:21]=[N:20][CH:19]=[CH:18][C:17]=2[C:16]([NH2:23])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:23][C:10]([NH:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[O:11])=[C:17]2[C:22]=1[CH:21]=[N:20][CH:19]=[CH:18]2
Reactant: O=C=NCc1cccc(F)c1
Reactant: Nc1ccc(Br)c2cnccc12
Product: O=C(NCc1cccc(F)c1)Nc1ccc(Br)c2cnccc12

Procedure:
The title compound was prepared using 1-fluoro-3-(isocyanatomethyl)benzene, the product of Example 73A and the procedure described in Example 73 (white solid, 108 mg, 65%). MS (ESI+) m/z 376 (M+H)+; MS (ESI−) m/z 374 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 4.39 (d, 5.8, 2H), 7.09 (m, 1H), 7.17 (m, 2H), 7.40 (m, 1H), 7.91 (d, J 8.5, 1H), 8.01 (d, J 6.1, 1H), 8.23 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.93 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C17H13BrFN3O: C, 54.56; H, 3.50; N, 11.23. Found: C, 54.64; H, 3.33; N, 11.19.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH2:12]([NH:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCC>[CH2:12]([N:19]([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCNCc1ccccc1
Reactant: Cc1ccc(N=C=O)c(C)c1
Solvent: CCCCCC
Product: CCCCN(Cc1ccccc1)C(=O)Nc1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4.89 g of 2,4-dimethylphenylisocyanate in 100 ml of hexane is added to a solution of 4.41 g of N-benzyl-n-butylamine in 150 ml of hexane, and the solution is stirred at room temperature for 2 hours and then evaporated. The residual solid is recrystallized from pentane to yield 1-benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)urea, m.p. 70°-71° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:19][C:18]3[C:13](=[C:14]([OH:20])[CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:19][C:18]3[C:13](=[C:14]([O:20][CH2:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2Cc3cccc(O)c3C2=O)cc1
Reactant: OCc1ccncc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(N2Cc3cccc(OCc4ccncc4)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(4-t-Butyl-phenyl)-7-hydroxy-2,3-dihydro-isoindol-1-one (0.201 g), 4-hydroxymethylpyridine (96 mg) and PPh3 (0.212 g) were dissolved in THF (20 mL). DIAD (0.16 mL) was added and the mixture was stirred at RT for 2 h. Solvent was evaporated and the residue was purified by silica gel chromatography (70 g, 100% EtOAc) to afford 2-(4-t-butyl-phenyl)-7-(pyridin-4-ylmethoxy)-2,3-dihydro-isoindol-1-one as a white solid. MS: (ES+) 373(M+H). Calc'd. for C24H24N2O2-372.46.
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].[CH3:9][C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[CH2:21][CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=1>O1CCOCC1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>[CH:5]([NH:8][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([CH2:22][CH2:21][C:11]2[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][O:14][C:10]=2[CH3:9])=[N:24][CH:25]=1)([CH3:7])[CH3:6]
Reactant: Cc1onc(-c2ccccc2)c1CCc1ccc(C(=O)O)cn1
Reactant: CC(C)N
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1CCc1ccc(C(=O)NC(C)C)cn1
Temperature: 90 °C
Reaction time: 15 h
Yield: 80.5 %

Procedure:
A solution of trimethyl aluminium (2 M in toluene, 0.32 mL, 0.65 mmol) was added dropwise to a solution of isopropylamine (38 mg, 0.65 mmol) in dioxane (1.5 mL) under argon and at room temperature. After 1 h a solution of 6-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-nicotinic acid (50 mg, 0.16 mmol) in dioxane (1.5 mL) was added and the reaction mixture warmed to 90° C. After 15 h, the reaction mixture was cooled and carefully diluted with Seignette salt solution (0.5 mL). The mixture was filtered, the filter cake washed with dichloromethane, then the combined filtrates were concentrated. Purification by chromatography (silica, dichloromethane:methanol 100:0 to 96:4) afforded the title compound (45 mg, 79%) as a light yellow oil. MS: m/e=350.5 [M+H]+.
Reaction SMILES: [S:1]([O:5][C:6]1[CH:26]=[CH:25][C:9]([O:10][C:11]2[C:22](I)=[CH:21][C:14]([CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])=[CH:13][C:12]=2[I:24])=[CH:8][C:7]=1[I:27])([OH:4])(=[O:3])=[O:2].C1C(C[C@H](N)C(O)=O)=CC(I)=C(OC2C=CC(O)=C(I)C=2)C=1.C1C(CC(N)C(O)=O)=CC(I)=C(OC2C=CC(O)=C(I)C=2)C=1.CO.CC1C=CC(S(NCl)(=O)=O)=CC=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>P([O-])([O-])([O-])=O>[CH:21]1[C:14]([CH2:15][C@H:16]([NH2:17])[C:18]([OH:20])=[O:19])=[CH:13][C:12]([I:24])=[C:11]([O:10][C:9]2[CH:25]=[CH:26][C:6]([O:5][S:1]([OH:4])(=[O:3])=[O:2])=[C:7]([I:27])[CH:8]=2)[CH:22]=1
Reactant: N[C@@H](Cc1cc(I)c(Oc2ccc(OS(=O)(=O)O)c(I)c2)c(I)c1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: NC(Cc1ccc(Oc2ccc(O)c(I)c2)c(I)c1)C(=O)O
Agent: N[C@@H](Cc1ccc(Oc2ccc(O)c(I)c2)c(I)c1)C(=O)O
Solvent: CO
Product: N[C@@H](Cc1ccc(Oc2ccc(OS(=O)(=O)O)c(I)c2)c(I)c1)C(=O)O

Procedure:
3,3'-T2S and [25I]T2S were prepared by the method of Eelkman-Rooda and co-workers (Eelkman-Rooda SJ, Kaptein E, VanLoon MAC, Visser TJ. 1988 "Development of a radioimmunoassay for triiodothyronine sulfate"), herein incorporated by reference in its entirety, but can be prepared by any number of methods known to those with skill in the art. L-3,3'-Diiodothyronine (L-T2) is purchased from Henning Berlin (Berlin, Germany). The radioactive [125I] T2 (S.A. 300-500 mCi/mg) was prepared by iodination of 3,3'-T2 (exchange reaction) using methods described in Nakamura Y, Chopra I J, Solomon DH. 1977 "Preparation of high specific activity radioactive iodothyronines and their analogues." Journal of Nuclear Medicine. 18:1112-1115, herein incorporated by reference in its entirety, but can be prepared by any of a number of methods known to those with skill in the art. In 10×75 mm disposable glass culture tubes, 10 μl of methanol containing 10-9 moles of the substrate (T2) were mixed with 25 μl of 0.4 M phosphate buffer (pH 6.2) containing approximately 1 mCi of I-125. The radioiodination reaction was started by adding 10 μl of 0.05M phosphate buffer (pH 6.2) containing 4 μg of chloramine-T. Two minutes later, the reaction was stopped by addition of 20 μl of a solution prepared by 1:10 dilution of saturated sodium metabisulfite in 0.05 M phosphate buffer (pH 6.2). The reaction mixture was next transferred to a column made from a 3-mL disposable plastic syringe filled with a suspension of Sephadex LH-20 up to 1.2 mL; the reaction vessel was washed once with 50 μl of 0.05 M phosphate buffer (pH 6.2), and washings were also transferred to the column. Unreacted radioiodine was removed by washing of the column with 1 mL of 0.05M phosphate buffer (pH 6.2) followed by 4 mL of water and 0.6 mL 99:1 (methanol: 2N NH4OH). The radioactive compounds were then eluted with 4 mL of 99:1 (methanol: 2N NH4OH) and were dried under a thin stream of air. The residue was dissolved in 100 μl of methanol (2N NH4OH) and applied to a paper strip to separate the radioiodinated iodothyronines.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccc(Cl)cc3)CC2)cc1-c1ccc(Cl)cc1

Procedure:
111 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg, 0.275 mmol), 1-(4-chlorophenyl)piperazine (74 mg, 0.275 mmol), DIPEA (0.072 mL, 0.413 mmol) and NaBH(OAc)3 (175 mg, 0.825 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.Cl.[F:40][C:41]1[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:48][S:49][C:50]1[N:55]=[C:54]([NH:56][S:57]([N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)(=[O:59])=[O:58])[CH:53]=[C:52]([O:66][CH3:67])[N:51]=1.CN1CCOCC1>CN(C=O)C>[F:40][C:41]1[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:48][S:49][C:50]1[N:55]=[C:54]([NH:56][S:57]([N:60]2[CH2:61][CH2:62][N:63]([C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:64][CH2:65]2)(=[O:58])=[O:59])[CH:53]=[C:52]([O:66][CH3:67])[N:51]=1
Reactant: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cc(NS(=O)(=O)N2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(tert-butoxycarbonyl)glycine (0.11 g) in DMF (10 mL) was added 1,3-Dicyclohexylcarbodiimide (0.14 g) and 1-hydroxybenzotriazole hydrate (94 mg). After stirring at room temperature for 1 h, a solution of N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]piperazine-1-sulfonamide, hydrochloride salt (the product of step i, 0.27 g) and N-methylmorpholine (78 μL) in DMF (5 mL) was added dropwise and stirring continued at room temperature for 24 h. The mixture was filtered, rinsed with DCM and the filtrate evaporated. The crude material was purified by column chromatography on silica gel using EtOAc/isohexane (3:2) as eluent to give the subtitle compound as a foam Yield: 0.24 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20](OC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:26])[F:27])[CH:3]=1
Reactant: COCCN
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O

Procedure:
This compound was prepared from methyl 7-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those those described in Example 9 and was purified by recrystallization from DMSO and MeOH. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.72 (1H, s), 10.28 (1H, brt, J=5 Hz), 8.47 (1H, s), 7.67 (1H, dd, J=9.3, 2.5 Hz), 7.59-7.51 (2H, m), 7.30 (1H, s), 4.29 (2H, s), 3.52-3.46 (4H, m), 3.26 (3H, s); HRMS calcd for C20H17F4N3O4+H+: 440.1233. Found: 440.1224.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[CH:26]=[N:27][NH:28][CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[CH:29]=[N:28][NH:27][CH:26]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(-c3cn[nH]c3)cccc21
Product: CC1c2cccc(-c3cn[nH]c3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[NH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[N:6]1([CH:7]=[CH:8][CH2:9][CH3:10])[CH2:4][CH2:3][CH2:2][CH2:1]1
Reactant: CCCC=O
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCC=CN1CCCC1
Reaction time: 8 h
Yield: 97 %

Procedure:
108 g of freshly distilled butyraldehyde were added dropwise at 0° C. to a mixture of 213 g of pyrrolidine and 213 g of potassium carbonate. The mixture was allowed to stand overnight at room temperature, diluted with 300 ml of toluene, and the residue was filtered off. The filtrate was then subjected to vacuum distillation at 85° to 90° C. (80 mbar), giving 102 g of 97% pure 1-pyrrolidinobutene, which corresponds to 63.7% of the theoretical yield).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[C:8]2[S:14][CH:15]=[CH:16][C:7]1=2)=[O:5].C(O)C.[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH:9]([OH:13])[C:8]2[S:14][CH:15]=[CH:16][C:7]1=2)=[O:5]
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c2ccsc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCCC(O)c2sccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1.0 g of 4-(2-chloro-4-nitrobenzoyl)-4,5,6,7-tetrahydro-8H-thieno[3,2-b]azepin-8-one in 10 ml of tetrahydrofuran is added 1 ml of ethanol and the mixture cooled to 0° C. To the mixture is added 0.129 g of sodium borohydride in portions and the mixture is stirred at 0° C. for 1 hour. To the mixture is added slowly 4.2 ml of saturated ammonium chloride solution at 0° C. After stirring at room temperature for 10 minutes, the solvent is removed under vacuum and 80 ml of ethyl acetate added to the residue. The mixture is washed with 20 ml each of H2O, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried (Na2SO4) and filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated under vacuum to give the product as a white glass.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([CH2:34][CH2:35][CH2:36][CH3:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([CH2:34][CH2:35][CH2:36][CH3:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2,6-di-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: C(OC([N:11]([CH2:32][CH2:33][O:34][CH3:35])[C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)=[N:16][CH:17]=1)=O)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[C].[Pd]>[CH3:35][O:34][CH2:33][CH2:32][NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)=[N:16][CH:17]=1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(N(CCOC)C(=O)OCc3ccccc3)cn2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(Oc2ccc(NCCOC)cn2)cc1
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of ethyl 3-(4-{5-[benzyloxycarbonyl(2-methoxyethyl)amino]pyridin-2-yloxy}phenyl}propionate (1.82 g, 3.8 mmol) in ethanol-ethyl acetate (10 mL-10 mL) was added under a nitrogen atmosphere 10% palladium-carbon (0.2 g), and the resulting solution was stirred for 3 hours under a hydrogen atmosphere at atmospheric pressure. The palladium-carbon was filtered off through Celite, and the filtrate was evaporated to yield 1.23 g of the title compound.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH:26]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>CC(N(C)C)=O.O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH:26]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: NC(CC(=O)O)c1cccnc1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1nc(C(=O)NC(CC(=O)O)c2cccnc2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 41.3 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.16 mmol) and 3-amino-3-pyridin-3-yl-propionic acid (52 mg, 0.31 mmol) (commercially available from Combi-Blocks SS-4195) in DMA (2 mL) was added sodium methoxide (17 mg, 0.31 mmol). The resultant suspension mixture was heated in a 150° C. oil bath for 2 h. After cooled, reaction mixture was diluted with water (75 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 30 mg (0.066 mmol) in 42% yield. LC-MS ESI−: 453 (M−1)−.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([N:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=2)[CH2:41][CH2:40]1)=[O:16]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Nc1onc(-c2ccccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 76.1 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (538 mg, 1.40 mmol, 76%) was obtained.
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][CH:7]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20](O)=[O:21]>>[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20]([NH:13][CH2:12][C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:14])[F:15])=[CH:7][CH:8]=1)=[O:21]
Reactant: NCc1ccc(OCC(F)(F)F)nc1
Reactant: Nc1cc(C(=O)O)ccn1
Agent: Cl
Product: Nc1cc(C(=O)NCc2ccc(OCC(F)(F)F)nc2)ccn1
Yield: 29 %

Procedure:
The title compound is prepared in 29% yield (182 mg, a white solid) from (6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (473 mg, 1.95 mmol) and 2-aminoisonicotinic acid (269 mg, 1.95 mmol) by the similar manner in Step-1 of Example-8.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:30][CH2:31][N:32]([C:8]([NH:7][C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:33][CH2:34]2)[S:27][CH:28]=1
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)c(F)c1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnn1)N1CCN(c2nc(-c3ccc(F)cc3F)cs2)CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 47.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (212 mg, 0.782 mmol), 1-[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.711 mmol) and diisopropylethylamine (0.248 ml, 1.42 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 136 mg (47.4%) of the desired product as a solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[OH:11][C:12]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][N:13]=1>>[OH:11][C:12]1[CH:17]=[C:16]([CH2:18][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH:15]=[CH:14][N:13]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=Cc1ccnc(O)c1
Product: O=C(O)c1ccccc1NCc1ccnc(O)c1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from anthranilic acid and 2-hydroxy-4-pyridinecarboxaldehyde (Tyger). 13C-NMR (DMSO-d6) δ 169.8, 162.4, 153.6, 150.2, 135.0, 134.2, 131.6, 115.8, 114.7, 111.5, 110.5, 104.0, 44.7.