Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([OH:8])[C@@H:6]([CH3:9])[CH2:5][N:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[C:28]([NH:29]C(=O)OCC3C=CC=CC=3)=[CH:27][C:26]3[C:21](=[CH:22][C:23]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][C:41]4=[O:46])=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:3]1.[H][H]>[Pd].CO>[NH2:29][C:28]1[C:19]([C:17]([NH:16][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:10]=2[N:4]2[CH2:5][C@H:6]([CH3:9])[C@@H:7]([OH:8])[C@H:2]([NH2:1])[CH2:3]2)=[O:18])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][C:41]1=[O:46])[CH:22]=2
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4=O)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](N)[C@@H]1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4=O)ccc3cc2N)C[C@@H](N)[C@@H]1O

Procedure:
A mixture of benzyl [2-[({4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(3-oxomorpholin-4-yl)quinolin-3-yl]carbamate (0.0068 g, 0.011 mmol) in of 3.0 mL of MeOH was hydrogenated in the presence of 8 mg of 10% Pd on carbon under a balloon of hydrogen at room temperature for 1 h. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C25H30N7O4 [M+H]+: m/z=492.2. found: 492.4.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl.[Cu]=O>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: Brc1ccccc1
Reactant: CC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(c2cn(-c3ccccc3)c3ccccc23)CC1
Yield: 77.5 %

Procedure:
A mixture of 3-(1-acetyl-4-piperidyl)indole (10.0 g), bromobenzene (6.48 g), potassium carbonate (5.70 g) and copper(II) oxide (0.26 g) in anhydrous N,N-dimethylformamide (10 ml) was refluxed for 30 minutes. The reaction mixture was cooled and diluted with chloroform, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was subjected to column chromatography on alumina (400 g) followed by elution with a mixture of toluene and ethyl acetate (20:1 V/V). The fractions containing the desired compound were combined and concentrated under reduced pressure to give 3-(1-acetyl-4-piperidyl)-1-phenylindole (10.19 g).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([OH:30])=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)C>[NH2:21][C:22]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Nc1ncnc(Cl)c1C(=O)O
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)O)n(-c3ccccc3)c(=O)c12
Yield: 29.7 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (270 mg, 0.89 mmol), 4-amino-6-chloropyrimidine-5-carboxylic acid (190 mg, 0.88 mmol, prepared according to Lan, Ruoxi et al from PCT Int. Appl. (2013), WO 2013040059 A1 20130321), DIEA (1.54 ml, 8.84 mmol) and cesium fluoride (403 mg, 2.65 mmol) were suspended in ethanol (10 ml) and the mixture was heated to reflux for 72 h. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography using SP1® Purification System (0% to 70%, ethyl acetate-methanol) to obtain 106 mg (27% yield) of the title compound. Purity: 90%.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[OH-:19].[Na+]>CN(C=O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:4]2[C:3](=[O:19])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH:14]=1
Reactant: Clc1c(-c2cccnc2)cnc2ccccc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(-c2cccnc2)c[nH]c2ccccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2N Hydrochloric acid(10 ml) was added to a DMF solution(5 ml) of 4-chloro-(3-pyridin-3-yl)quinoline(0.51 g), and the mixture was stirred at 80° C. for 1 hour. After the reaction mixture was cooled to room temperature, 2N sodium hydroxide aqueous solution(10 ml) was added dropwise under ice cooling. The mixture was stirred. The precipitated insoluble matter was separated, washed with water and ether, and dried to give the title compound(0.35 g) as a pale whitish purple powder.
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:6]=2[C:5]=1[C:15]([O:17]C)=O)=[C:2]=[S:3].[N:19]1([CH2:24][CH2:25][CH2:26][NH2:27])[CH:23]=[CH:22][N:21]=[CH:20]1>>[N:19]1([CH2:24][CH2:25][CH2:26][N:27]2[C:15](=[O:17])[C:5]3[C:6]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: COC(=O)c1c(N=C=S)sc2c1CCCCCC2
Reactant: NCCCn1ccnc1
Product: O=c1c2c3c(sc2[nH]c(=S)n1CCCn1ccnc1)CCCCCC3

Procedure:
The compound was synthesized starting from methyl 4,5,6,7,8,9-hexahydro-2-isothiocyanatocycloocta[b]thiophene-3-carboxylate (0.004 g, 0.01 mmol) and 3-(1H-imidazol-1-yl)propan-1-amine (0.002 g, 0.01 mmol) as described above.
Reaction SMILES: C[C:2](C)([C:6]([O-:8])=[O:7])C([O-])=O.[H-].[Na+].[C:12]12[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17][C:16](=[O:23])[O:15][C:13]2=O.Cl.[CH3:25]N(C=O)C>>[OH:15][C:13]1[C:12]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16](=[O:23])[C:2]=1[C:6]([O:8][CH3:25])=[O:7]
Reactant: CN(C)C=O
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1c(O)c2ccccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Dimethylmalonate (2.2 mL, 19.2 mmol) was added slowly to a suspension of 60% sodium hydride in mineral oil (0.81 g, 20.3 mmol) in anhydrous DMF (50 mL) at −10° C. under nitrogen. After stirring at room temperature for 30 minutes, isatoic anhydride (3.0 g, 18.4 mmol) was added, and the reaction was heated at 115° C. for 2.5 hours. The reaction was cooled to room temperature, then poured into ice water (500 mL) and acidified to pH 2 with 2M HCl. The resultant precipitate was collected by filtration to give crude methyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (2.89 g, 72%), which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ3.86 (s, 3H), 7.23 (m, 2H), 7.63 (m, 1H), 7.94 (dd, J=0.8, 8.0 Hz, 1H), 11.55 (s, 1H), 13.33 (s, 1H). MS 220 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([OH:11])[C:9]#[CH:10].C(N(C(C)C)CC)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1COCC1.[Cu](I)I>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:10]#[C:9][CH2:8][OH:11])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C#CCO
Agent: I[Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: OCC#Cc1cccnc1
Reaction time: 18 h
Yield: 79.3 %

Procedure:
A solution of 3-bromopyridine (2.0 g, 12.6 mmol), propargyl alcohol (1.1 mL, 19 mmol), diisopropylethylamine (3.2 mL, 23 mmol), copper iodide (133 mg, 0.7 mmol) and tri-(t-butyl)phosphine (286 mg, 1.4 mmol) in degassed THF (10 mL) was treated with Pd(CH3CN)2Cl2 (181 mg, 0.7 mmol) at 25° C. under N2. After 18 h, the reaction mixture was filtered through celite, washed with ethyl acetate (2×100 mL), and concentrated in vacuo. Purification by flash chromatography (EtOAc) afforded the title compound (1.33 g, 80%) as a yellow oil. MS 134 (M+H)+.
Reaction SMILES: [H][H].[NH3:3].Cl[C:5]1[N:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[C@@H:25]1[O:37][C@H:36]([CH2:38][O:39]C(=O)C)[C@@H:31]([O:32]C(=O)C)[C@H:26]1[O:27]C(=O)C>>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:12]2[N:13]=[C:5]([NH2:3])[C:6]3[N:7]=[CH:8][N:9]([C:10]=3[N:11]=2)[C@@H:25]2[O:37][C@H:36]([CH2:38][OH:39])[C@@H:31]([OH:32])[C@H:26]2[OH:27])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(OCc4ccc([N+](=O)[O-])cc4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N
Reactant: [H][H]
Product: Nc1nc(OCc2ccc([N+](=O)[O-])cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 80 %

Procedure:
A compound having a structure of the above formula was prepared where the substituents R1 and R2 are hydrogen and R3 is 4-nitrobenzyl (—CH2(4-nitro)C6H4). The compound (C17H18N6O7) was prepared by reaction of ammonia with 6-chloro-2-(4-nitrobenzyl)oxy-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (Example 4) as described in Example 2, Step E. The final product was isolated in 80% yield as a solid with a melting point of 174-176° C. 1H-NMR (DMSO-d6): δ 3.5 (m, 1H); 3.6 (m, 1H); 3.8 (d, 1H, J=4); 4.1 (m, 1H); 4.56 (m, 1H); 5.16 (m, 2H); 5.4 (d, 1H, J=6); 5.47 (s, 2H); 5.77 (d, 1H, J=6); 7.43 (bs, 2H); 7.7 (d, 2H, J=8); 8.18 (s, 1H); 8.24 (d, 2H, J=8).
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].C([Mg]Cl)(C)C.Br[C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2.Cl>C1COCC1.C1COCC1.CCCCCC.CCOC(C)=O>[O:15]=[C:4]([C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Brc1cnc2ccccc2c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1cnc2ccccc2c1
Temperature: -10 °C

Procedure:
(S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (2.5 g, 10.76 mmol) was suspended in THF (5 mL) and stirred at −10° C., isopropylmagnesium chloride 2.0M solution in THF (5.4 ml, 10.80 mmol) was added and a solution was formed. To this solution was added a solution of Lithium tri(3-quinolinyl)magnesiate in THF/Hexane, prepared from 3-bromoquinoline (1.471 ml, 10.81 mmol) according to the procedure described by Sylvain Dumouchel et-al. in Tetrahedron 59 (2003) 8629-8640. The mixture was stirred at −10° C. for 30 min and was the allowed to reach r.t. and stirred over night, 15 h. The reaction mixture, a clear red solution, was slowly poured into ice-cooled 1M HCl (aq) (100 mL). EtOAc (150 mL) was added and the mixture was stirred for a few min, the water phase was extracted once with EtOAc, the combined EtOAc solutions was further washed with saturated NaHCO3 (aq) and brine. The crude material was purified by flash-chromatography on silica using a gradient of 0% to 40% EtOAc in Heptane. The obtained material was the further purified by HPLC to afford the subtitle compound as a yellow sticky oil. Yield 1.6 g (49%)
Reaction SMILES: [Ca].[C:2]([C@@H:5]([C@H:7]([C:9]([O-:11])=[O:10])[OH:8])[OH:6])([O-:4])=[O:3].[C:12]([O-:19])(=[O:18])/[CH:13]=[CH:14]\[C:15]([OH:17])=[O:16].[Na+]>>[C:2]([CH:5]([CH:7]([C:9]([O-:11])=[O:10])[OH:8])[OH:6])([O-:4])=[O:3].[C:12]([O-:19])(=[O:18])/[CH:13]=[CH:14]\[C:15]([O-:17])=[O:16]
Reactant: O=C([O-])/C=C\C(=O)O
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Ca]
Agent: [Na+]
Product: O=C([O-])/C=C\C(=O)[O-]
Product: O=C([O-])C(O)C(O)C(=O)[O-]

Procedure:
In the production of HOPTC and DOOHC it is preferred that calcium D, L-tartrate and monosodium maleate slurry obtained from the tartrate/maleate removal step is added to the calcium maleate while heating to a boil at atmospheric pressure. The mixture is held at boiling for about 15 minutes to ensure conversion of all of the calcium carbonate to the maleate. The mixture is then charged to the synthesis reactor for the preparation of additional HOPTC and DOOHC. During transfer to the synthesis reactor water may be evaporated to reduce volume.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[C:14]([O:28][CH3:29])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)[CH:42]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C1(P([Pd-4](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)C=CC=CC=1>[CH3:29][O:28][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:38]3[CH:39]=[N:40][N:41]([CH:43]4[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]4)[CH:42]=3)[CH:3]=[C:4]2[N:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(-c5cnn(C6CCN(C(=O)OC(C)(C)C)CC6)c5)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a stirred suspension of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine (0.20 g, 0.40 mmol) in N,N-dimethylformamide (8 mL) and water (2 mL) was added tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.15 g, 0.40 mmol), potassium carbonate (0.22 g, 1.59 mmol), and tetrakis(triphenylphosphino)palladium(0) (0.021 g, 0.018 mmol). The mixture was heated to 100° C. After 1 h, the reaction mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was concentrated, and the residue purified via silica gel chromatography (5% methanol/dichloromethane elute) to provide 0.15 g (60%) of tert-butyl 4-(4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][CH:10]=2)[O:3]1.[CH:20](OCC)(OCC)OCC>C(O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:19])([CH3:1])[O:3][B:4]([C:9]2[CH:18]=[CH:17][C:12]([C:13]3[O:14][CH:20]=[N:16][N:15]=3)=[CH:11][CH:10]=2)[O:5]1
Reactant: CCOC(OCC)OCC
Reactant: CC1(C)OB(c2ccc(C(=O)NN)cc2)OC1(C)C
Solvent: CCO
Product: CC1(C)OB(c2ccc(-c3nnco3)cc2)OC1(C)C

Procedure:
10 g (38 mmol) of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzohydrazide are dissolved in 30 g (20 mmol) of triethyl orthoformate, and the mixture is heated to reflux. The ethanol formed during the reaction is continuously removed by distillation. After the mixture has cooled, the product crystallizes out, is filtered off and washed with a little ethanol. Yield: 8.7 g (32 mmol, 84%). An analogous procedure is carried out using the compounds of the formula (II) shown in Table 4.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]([NH:18][CH2:19][C:20]([OH:22])=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[CH2:31]([NH:33][CH2:34][CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[CH3:32]>O1CCCC1>[CH2:31]([N:33]([C:20](=[O:22])[CH2:19][NH:18][C:16]([O:15][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:17])[CH2:34][CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[CH3:32]
Reactant: CCNCCc1c[nH]c2ccccc12
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CCc1c[nH]c2ccccc12)C(=O)CNC(=O)OCc1ccccc1
Temperature: -15 °C
Yield: 101.6 %

Procedure:
30 ml of anhydrous tetrahydrofuran and 1.05 g of triethylamine are added to 2.17 g of N-benzyloxycarbonyl-glycine, and 1.43 g of isobutyl chloroformate are added dropwise thereto at -15° C. under stirring. A solution of 1.96 g of N-ethyl-tryptamin (i.e., 3-(2-ethylamino)ethylindole) in 40 ml of anhydrous tetrahydrofuran is added dropwise to the mixture at the same temperature, and said mixture is stirred at 0° C. for one hour and further stirred at room temperature for 16 hours. After the reaction, the reaction mixture is evaporated to remove solvent. The residue (oil) is purified by silica gel chromatography (Solvent: ethyl acetate-chloroform (1:1). 4.0 g of N-ethyl-N-(N-benzyloxycarbonylglycyl)-tryptamine are thereby obtained as a colorless oil. Yield: 100%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br>>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Fc1ccccc1CBr
Product: O=[N+]([O-])c1ccc(OCc2ccccc2F)cc1
Yield: 74 %

Procedure:
Prepared in analogy to example 8 from 4-nitrophenol and 2-fluoro-benzylbromide. Colorless solid. Yield=74%. MS: m/e=247.1 (M+).
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:20](O)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CCN(C(C)C)C(C)C.[NH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:20]([NH:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: NCC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of Boc-(D)-Arg(Tos)-OH (1 g, 2.34 mmol) in CH2Cl2 (10 mL) was added DIEA (1 mL) at 0° C. To the clear solution was added Gly-OBn.eHCl (0.52 g, 2.58 mmol) and BOP (1.2 g, 2.8 mmol). The solution was stirred for 4 h at 0° C. Solvents were evaporated and residue was dissolved in a mixture of EtOAc (100 mL) and water (20 mL). The organic layer was washed with sat. NaHCO3 (10 mL), water (10 mL), 1N HCl (10 mL) and sat. NaCl (3×10 mL), dried with MgSO4, filtered and evaporated. The solid residue was purified by column chromatography on silica gel (EtOAc) to give 1.12 g of the title compound as a powder. ES-MS (M+H)+=576.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[CH:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1c[nH]c(Sc2cc(Cl)cc(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Sc2cc(Cl)cc(Cl)c2)c1

Procedure:
Methyl 5-(3,5-dichlorophenylthio)pyrrole-3-carboxylate (2.5 g.) was combined with 25 ml. of methanol and 25 ml. of 1 N sodium hydroxide and refluxed for 3 hours. The methanol was allowed to evaporate, the aqueous residue diluted with approximately one volume of water and washed twice with ether. The aqueous phase was acidified with conc. hydrochloric acid and the product extracted into ethyl acetate. The two ethyl acetate extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to crude product (1.84 g., m.p. 169°-172° C.). Recrystallization from chloroform afforded purified 5-(3,5-dichlorophenylthio)-pyrrole-3-carboxylic acid (1.3 g., m.p. 175°-177° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].[I:14]N1C(=O)CCC1=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:13]([I:14])=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 235a (1.04 g, 5.9 mmol) in 12 mL anhydrous DMF was added N-iodosuccinimide (1.46 g, 6.49 mmol) and the solution stirred at room temperature for 16 hours. The solvent was evaporated and the residue suspended in water and filtered. The collected solid was triturated with dichloromethane and the mixture filtered. The dichloromethane filtrate was concentrated to a brown powder that was carried on without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([C:27]#[N:28])=[CH:3][CH:4]=3)[CH2:11][CH2:12]2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc(CCN2CCN(CCc3ccc(Br)cc3)CC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)cc1

Procedure:
A solution of 1-[2-(4-bromophenyl)ethyl]-4-[2-(4-nitrophenyl)ethyl]piperazine (100 mg, 0.24 mmol), Zinc cyanide (84 mg, 0.72 mmol), and tetrakis(triphenylphosphine)palladium in DMF (1 mL) was heated to 85° C. for 1 hour. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 365 (M+1)+. (0.079 μM)
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:24][CH:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: CCOC(=O)CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)CC(C)NCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (30 mg, 0.097 mmol), ethyl 3-aminobutanoate (CAS no. 5303-65-1) (19 mg, 0.145 mmol), and acetic acid (17 mg, 0.291 mmol) were dissolved in dichloroethane (2 mL). The mixture was stirred at r.t. for 10 min under nitrogen atmosphere. Then NaBH(OAc)3 (41 mg, 0.194 mmol) was added to the mixture and the mixture was stirred at r.t. for 15 h. Then saturated NaHCO3 was added to the mixture to adjust the pH to 8. The mixture was extracted with ethyl acetate and the organic layer was purified by silica gel column chromatography using dichloromethane:methanol 10:1 to give product ethyl 3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)butanoate (40 mg, 88%) as a slight yellow solid. ESI-MS: 426.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.70-7.65 (m, 3H), 7.41 (d, 1H), 7.13-7.09 (m, 2H), 4.28-4.23 (m, 1H), 4.12 (q, 2H), 3.98-3.88 (m, 2H), 3.22-3.18 (m, 1H), 2.53-2.42 (m, 2H), 2.28-2.25 (m, 2H), 1.90-1.87 (m, 2H), 1.45-1.42 (m, 2H), 1.26-1.09 (m, 9H), 0.90 (s, 9H).