Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[CH:19][C:18]4=[CH:21][CH:22]=[C:23]([C:24]5[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=5)[N:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:31][S:32]([CH2:35][CH2:36][NH2:37])(=[O:34])=[O:33].Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:31][S:32]([CH2:35][CH2:36][NH:37][CH2:29][C:27]1[O:28][C:24]([C:23]2[N:17]3[C:18]([CH:19]=[N:20][C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:9][CH:10]=4)=[N:16]3)=[CH:21][CH:22]=2)=[CH:25][CH:26]=1)(=[O:34])=[O:33]
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccc(C=O)o5)n4n3)cc2)CC1
Reactant: CS(=O)(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccc(CNCCS(C)(=O)=O)o5)n4n3)cc2)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
Into an 8-dram vial, 5-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-furan-2-carbaldehyde (97.57 mg, 0.2424 mmol), 2-Methanesulfonyl-ethylamine; hydrochloride (0.2322 g, 1.454 mmol), 1,2-Dichloroethane (15.0 mL), and Acetic acid (100.0 uL, 1.759 mmol) were added and heated at 45° C. overnight. Sodium triacetoxyborohydride (0.1541 g, 0.7273 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (5 to 25% methanol). The collected fractions afforded (7-{5-[(2-Methanesulfonyl-ethylamino)-methyl]-furan-2-yl}-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as a yellow solid (45 mg, 36%). LCMS (E/I+) 510.08 (M+H). NMR 1H (DMSO-d6)-9.23 (s, 1H), 8.91 (s, 1H), 7.63 (d, 2H, J=8.69 Hz), 7.19 (d, 1H, J=3.02 Hz), 7.00 (d, 1H, J=4.57 Hz), 6.97 (d, 2H, J=9.42 Hz), 6.90 (d, 1H, J=5.03) Hz, 6.53 (d, 1H, J=3.66 Hz), 3.81 (s, 2H Hz) 3.25 (t, 2H, J=6.40 Hz), 3.10 (t, 4H, J=5.03 Hz), 3.02 (s, 3H), 2.97 (t, 2H, J=6.40 Hz), 2.49 (t, 4H, J=5.03), 2.23 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9](OCC)=[O:10])=[C:4]([F:14])[CH:3]=1.[NH3:15]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([NH2:15])=[O:10])=[C:4]([F:14])[CH:3]=1
Reactant: CCOC(=O)c1[nH]c(=O)c(Br)cc1F
Reactant: N
Solvent: CCO
Product: NC(=O)c1[nH]c(=O)c(Br)cc1F
Temperature: 45 °C

Procedure:
In a round bottom flask charged with ethyl 5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxylate (4, 0.8 g, 3.03 mmol) at 0° C. was added liquid ammonia (15 mL, 3.03 mmol) in ethanol (5 mL). The stirred reaction mixture was warmed to 45° C. for 2 h. After the ester was completely consumed liquid ammonia and ethanol was evaporated under reduced pressure. Methanol was added and the mixture was refluxed for 2 h and filtered while hot. The volume of the filtrate was reduced by ⅔ and to the remaining methanol was added diethyl ether until solid precipitated. The solid was filtered and dried under vacuum to afford 5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxamide (5) as a light brown solid. Yield: 0.6 g, 85%; 1H NMR (400 MHz, DMSO-d6) δ 7.88-7.86 (m, 1H), 7.67 (s, 1H), 7.50 (s, 1H).
Reaction SMILES: C(O[C@@H:5]1[O:17][C@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[Br-:23]>C1C=CC=CC=1.[N+](C)([O-])=O.C(OCC)(=O)C>[C:8]([O:7][C@@H:6]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[O:17][C@H:5]1[Br:23])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [Br-]
Solvent: C[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Br)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
A solution of 10 g of 5,6-O-isopropylidene-1,2',3,6'-tetrakis-N-(trifluoroacetyl)neamine (3) in 330 ml of benzene and 220 ml of nitromethane is heated to boiling and 110 ml of distillate collected. 2,3,5-Tri-O-acetyl-β-D-ribofuranosyl bromide is prepared from 16.5 g of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose, as described above. The bromide is dissolved in 30 ml of nitromethane. One third of this solution and 7 g of mercuric cyanide is added to the original reaction mixture. The mixture is heated to reflux. Two similar additions of bromide and mercuric cyanide are made after 1 and 2 hours of reflux. The mixture is refluxed a final hour. The cooled reaction mixture is diluted with 750 ml of ethyl acetate and extracted with two 500 ml portions of 5% KHCO3 solution. The organic layer is washed with brine and filtered through Na2SO4. The solvent is evaporated under vacuum. The residue is chromatographed over 1 kg of silica gel, and eluted with chloroform-methanol (20:1). Fractions of 50 ml are collected and monitored by tlc. Fractions 1-30 contain fast moving impurities and are discarded. Fractions 30-40 (27A) weigh 13.4 g, while fractions 41-48 (27B) weigh 3.23 g. A 12.4 g portion of 27A is rechromatographed over 1 kg of silica gel using chloroform-methanol (30:1) for elution. The center cut based on tlc of the fractions is combined and evaporated to give 6.66 g of blocked analog (12β). CMR data, after removal of the blocking group as described infra, shows this compound to be chiefly the 3' β isomer.
Reaction SMILES: [C:1]([O:9]CC)([O:6][CH2:7][CH3:8])(OCC)[CH3:2].[CH3:12][C:13]1([CH3:24])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15](=[CH:21][CH2:22]O)[CH2:14]1.C(O)(=O)CC>>[CH3:19][C:17]1([CH3:20])[CH2:18][C:13]([CH3:24])([CH3:12])[CH2:14][C:15]([CH2:2][C:1]([O:6][CH2:7][CH3:8])=[O:9])([CH:21]=[CH2:22])[CH2:16]1
Reactant: CC1(C)CC(=CCO)CC(C)(C)C1
Reactant: CCOC(C)(OCC)OCC
Solvent: CCC(=O)O
Product: C=CC1(CC(=O)OCC)CC(C)(C)CC(C)(C)C1
Temperature: 145 °C
Yield: 72.4 %

Procedure:
A mixture of triethyl orthoacetate (18.6 ml, 102 mmol), 2-(3,3,5,5-tetramethyl-cyclohexylidene)ethanol (3) (4.63 g, 25.4 mmol) and propionic acid (0.19 ml, 2.5 mmol) was heated at 145° C. for 10 h. Ethanol was distilled off from the mixture in the course of reaction. The reaction mixture was cooled and poured into water (100 ml). The aqueous phase was extracted with hexane (250 ml) and the combined organic phases were washed with 5% aqueous KHSO4 (50 ml) and brine (50 ml). The extract was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (light petroleum ether and light petroleum ether-ethyl acetate, 100:2) to give 16 (4.64 g, 73%) as an oil. 1H-NMR (CDCl3, TMS): 0.91 (6H, s, 3,5-CH3); 1.01 (6H, s, 3,5-CH3); 1.23 (3H, t, 7 Hz, ethyl CH3) 1.00-1.30 (4H, m, 4-CH2 and 2,6-CH); 1.86 (2H, d, 13 Hz, 2,6-CH); 2.22 (2H, s, CH2C═O); 4.08 (2H, q, 7 Hz, ethyl CH2); 5.06 and 5.07 (total 2H, both d, 11 and 17.5 Hz, ═CH2) and 5.95 ppm (1H, dd, 11 and 17.5 Hz, —CH═).
Reaction SMILES: [CH3:1][S-:2].[Na+].[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([C@@H:16]2[CH2:18][O:17]2)[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].O>C1COCC1>[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([C@@H:16]([OH:17])[CH2:18][S:2][CH3:1])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H]2CO2)C1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
Sodium methyl mercaptide (296 mg, 4.2 mmol) was dissolved in THF (1.0 mL), and the mixture was stirred for 10 minutes at room temperature. (S)—(R)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (300 mg, 1.41 mmol) was dissolved in THF (0.4 mL) and added to the mixture. The resulting solution was placed in a microwave reactor for 30 minutes at 100° C., then cooled to room temperature. Hexanes (3×10 mL) was added, followed by water (10 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (0-100% EtOAc in hexanes) to yield the title compound as a clear oil (207 mg).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][Cl:9].Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:37][CH2:36][N:35](CC4C=C5C(C=CC(=O)O5)=CC=4)[CH2:34][CH2:33]3)[N:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[ClH:9].[ClH:1].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=4)[CH2:34][CH2:33]3)[N:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: ClCc1ccccn1
Reactant: COc1ccc(C2=NN(C3CCN(Cc4ccc5ccc(=O)oc5c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(Cc4ccccn4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from compound A1 and 2-picolylchloride hydrochloride as described for compound 18. M. p. 214-216° C.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:8].[Na+].[CH2:10]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>C(O)C.O>[CH2:10]([O:7][C:1]1[CH:6]=[CH:5][C:4]([CH:21]=[C:20]2[CH2:23][CH2:24][CH2:17][C:18](=[CH:21][C:20]3[CH:23]=[CH:24][C:17]([O:16][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:18][CH:19]=3)[C:19]2=[O:8])=[CH:3][CH:2]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: [OH-]
Reactant: CCCCCCOc1ccc(C=O)cc1
Reactant: O=C1CCCCC1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCOc1ccc(C=C2CCCC(=Cc3ccc(OCCCCCC)cc3)C2=O)cc1
Reaction time: 0.33 h

Procedure:
Cyclohexanone (2.6 ml, 0.025 mol) was dissolved in ethanol (5 ml), and was added to sodium hydroxide (0.38 g, 0.01 mol) dissolved in water (6 ml) and ethanol (2 ml) and was left to stir for 20 min. 4-Hexyloxybenzaldehyde (10 ml, 0.048 mol), dissolved in ethanol (40 ml), was added and the mixture was stirred at room temperature for 16 h. A yellow crystalline solid was isolated by vacuum filtration and was washed with cold ethanol and dried in a vacuum oven. Yield=4.32 g, 36%. 1H NMR and 13C NMR showed expected signals.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:6]=[N:7][C:8]([NH:11][CH2:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH3:15])[CH3:14])=[CH:9][CH:10]=1)=O.[C:23]([NH:26][C:27]([NH2:29])=[NH:28])(=[O:25])[CH3:24]>C(#N)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]([CH3:15])([CH3:14])[CH2:12][NH:11][C:8]2[N:7]=[N:6][C:5]([C:3]3[N:28]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[NH:29][CH:2]=3)=[CH:10][CH:9]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(CNc1ccc(C(=O)CBr)nn1)c1ccc(F)cc1
Reactant: CC(=O)NC(=N)N
Solvent: CC#N
Product: CC(=O)Nc1nc(-c2ccc(NCC(C)(C)c3ccc(F)cc3)nn2)c[nH]1
Temperature: 100 °C
Yield: 63.3 %

Procedure:
To a 3 mL microwave reaction vial was added 2-bromo-1-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)ethanone (125 mg, 0.3 mmol, 1.0 equiv), acetyl guanidine (90 mg, 0.6 mmol, 2.0 equiv) and acetonitrile (2 mL). The reaction was heated in a microwave reactor at 100° C. for 13 min. The reaction was filtered and directly purified by reverse phase column chromatography to afford N-(4-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1H-imidazol-2-yl)acetamide (70 mg) as an white solid. m/z=369.2 [M+H]+.
Reaction SMILES: Cl.Cl[CH:3]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27][CH:3]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: COc1ccc(CCC(Cl)Cn2ccnc2)cc1
Reactant: Sc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(CCC(Cn2ccnc2)Sc2ccccc2Cl)cc1
Reaction time: 8 h

Procedure:
A mixture of 1-[2-chloro-4-(4-methoxyphenyl)-n-butyl]imidazole hydrochloride (prepared from 2.00 g. of alcohol as in Preparation C), 2-chlorothiophenol (2.80 g) and anhydrous potassium carbonate (2.70 g) in acetone (50 ml) was heated under reflux with stirring overnight. After removal of the solvent under reduced pressure, ether (150 ml) was added and the extract washed with water (2×30 ml) and dried (MgSO4) and the solvent removed to afford 1-[2-(2-chlorophenylthio)-4-(4-methoxyphenyl)-n-butyl]imidazole. Dropwise addition of 70% nitric acid (d-1.42) to an ethereal solution of this material until precipitation was complete gave the nitrate salt of 1-[2-(2-chlorophenylthio)-4-(4-methoxyphenyl)-n-butyl]imidazole, recrystallized from acetone/ethyl acetate as colorless microcrystals (3.10 g), mp 131.5°-133.5° C.
Reaction SMILES: C(O)C.FC(F)(F)S(O[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:11]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=O)=O.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[N:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:10]([C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)=[C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]1
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(c2ccncc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C

Procedure:
To a 1:1 (v/v) ethanol:toluene solution (0.18 M) of 1-(1,1-dimethylethyl) 3-ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (1 eq.) and 4-pyridinylboronic acid (1.1 eq.) was added sodium carbonate (2 M aq. solution, 2.6 eq.). The suspension was evacuated and back-filled with N2. Finally, tetrakis(triphenylphosphine)palladium(0) (0.04 eq.) was added in one rapid portion and the reaction suspension was heated at 80° C. for 18 h. The reaction was then quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 80:20 (v/v) Hex:EtOAc→ EtOAc) afforded the title compound as a golden yellow oil.
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[NH:26][CH2:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=1)=O)(C)(C)C>CCOC(C)=O>[ClH:1].[C:14]1([C@H:13]2[C@@H:12]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:11][C:10]([NH:26][CH2:27][C:28]3[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=3)=[N:9]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1C(NCc2cc(F)c(F)c(F)c2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1cc(CNC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride is bubbled into a solution of 83 (0.44 g, 0.91 mmol) in EtOAc (15 mL) for 1 min, and the solution is stirred at RT overnight. The solvent is removed by rotary evaporation, and the residue crystallized from dichloromethane and Et2O give 0.21 g of the product 84. 1H NMR (DMSO-d6) δ 9.40 (s, 1H), 9.14 (t, 1H), 7.88 (s, 1H), 7.20-6.80 (m, 8H), 6.80-6.55 (m, 4H), 5.07 (s, 2H), 4.70-4.50 (m, 2H); MS: m/z 382 (M++1).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][CH3:18])[CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:19][I:20]>O1CCOCC1>[I-:20].[CH3:19][N+:13]1[C:14]([CH3:16])=[CH:15][C:10]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:11][C:12]=1[NH:17][CH3:18]
Reactant: CI
Reactant: CNc1cc(-n2ccc3ccccc32)cc(C)n1
Solvent: C1COCCO1
Product: CNc1cc(-n2ccc3ccccc32)cc(C)[n+]1C
Product: [I-]
Temperature: 90 °C
Yield: 27 %

Procedure:
A mixture of 4-(1-indolyl)-6-methyl-2-methylaminopyridine (0.35 g, 1.48 mM), methyl iodide (0.5 ml) and dioxane (20 ml) was heated at 90° C. for 15 hours. The mixture was cooled. The solid was collected by filtration, washed with dioxan (10 ml) and then recrystallised from methanol. There was thus obtained 1,6-dimethyl-4-(1-indolyl)-2-methylaminopyridinium iodide (0.15 g, 27% yield), m.p. 275°-277° C.; microanalysis, found: C,49.3; H,4.7; N,10.3%; C16H18N3I. 0.5H2O requires: C,49.5; H,4.9; N,10.8%; NMR: 2.66(3H,s,CH3), 3.1(3H,d, NHCH3), 3.67(3H,s,N+CH3), 6.9(1H,d, indole-3H), 7.05(1H,d,pyridine-3H), 7.2-7.4(3H, complex, pyridine 5-H and aromatic), 7.7(1H,d, aromatic), 7.9-8.0(2H, complex, aromatic and indole-2H), 8.15-8.25(1H,br,NH).
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)=O.CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:25][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1
Reactant: CCCCCc1ccc(-c2ccc(C=O)cc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCc1ccc(-c2ccc(C=C(Br)Br)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 54.9 %

Procedure:
A solution of 15.3 g of tetrabromomethane in 150 ml of methylene chloride was placed at 0° C. in a sulphonation flask under argon gasification and treated within 5 minutes with a solution of 12.1 g of triphenylphosphine in 50 ml of methylene chloride. After completion of the addition, the clear orange reaction solution was stirred at 0° C. for a further 5 minutes and then a solution of 5.80 g of 4-formyl-4'-pentylbiphenyl in 50 ml of methylene chloride was added dropwise within 10 minutes. After stirring at 0° C. for a further 45 minutes, the yellow-orange mixture was poured into 1000 ml of hexane and the precipitate which thereby separated was filtered off (rinsing with hexane). The concentrated filtrate was digested with 400 ml of hexane, left to stand at 0° C. for 18 hours, filtered (rinsing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.5 bar) of the residue (9.8 g) on silica gel with hexane gave 5.15 g (55%) of 4-(2,2-dibromovinyl)-4'-pentylbiphenyl as colourless crystals (purity 99.1%); m.p. 95° C.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([NH2:20])=[O:19])=[O:15])[CH2:11][CH2:12][CH3:13])=[O:8].[H][H]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([NH2:20])=[O:19])=[O:15])[CH2:11][CH2:12][CH3:13])=[O:8]
Reactant: CCC[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(N)=O
Yield: 94.5 %

Procedure:
1.42 g (3.1 mmoles) of Z-Glp-Nva-Pro-NH2 are dissolved in 30 ml of methanol. 0.2 g of a 10% palladium-on-carbon catalyst are added to the solution, and hydrogen is bubbled through the mixture for 30 minutes. The catalyst is filtered off, the filtrate is evaporated, and the amorphous, solid residue is triturated with ether. The resulting crude product is dissolved in water, the solution is decolourized, filtered, and the clear filtrate is freeze-dried. 0.95 g (94%) of Glp-Nva-Pro-NH2 are obtained; Rf4 =0.36, [α]D25 =-87.0° (c=1%, in acetic acid). Amino acid analysis: Glu: 0.97 (1.0), Nva: 1.09 (1.0), Pro: 1.00 (1.0).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cccc(CO)c1
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a solution of 3-nitrobenzaldehyde (5 g, 33.1 mmol) in MeOH (25 mL) at ambient temperature was added NaBH4 (1.25 g, 33.1 mmol) and the resulting mixture was stirred for 30 min. The reaction mixture was quenched with water. The product was extracted with CH2Cl2 thrice and the combined organic extracts were washed with H2O followed by brine, dried over Na2SO4 and concentrated under reduced pressure to furnish without purification 5 g of compound (xB). 1H NMR (CDCl3): δ 8.27 (s, 1H), 8.17 (dd, 1H), 7.73 (dd, 1H), 7.57 (t, 1H), 4.85 (s, 2H), 2.07 (s, 1H). MS (m/z): 154 [M+H]+.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[CH3:13][N:14]1[CH:19]2[CH2:20][CH2:21][CH:15]1[CH2:16][CH:17]([O:22][C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=3)[N:24]=1)[CH2:18]2.[NH2:42][C:43]1[CH:51]=[CH:50][C:46]([C:47]([NH2:49])=[O:48])=[CH:45][CH:44]=1.CCN(CC)CC>C(Cl)Cl>[CH3:13][N:14]1[CH:15]2[CH2:21][CH2:20][CH:19]1[CH2:18][CH:17]([O:22][C:23]1[N:28]=[C:27]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[N:26]=[C:25]([C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:5](=[O:11])[NH:42][C:43]4[CH:51]=[CH:50][C:46]([C:47]([NH2:49])=[O:48])=[CH:45][CH:44]=4)=[CH:39][CH:40]=3)[N:24]=1)[CH2:16]2
Reactant: CN1C2CCC1CC(Oc1nc(-c3ccc(N)cc3)nc(N3CCOCC3)n1)C2
Reactant: NC(=O)c1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C2CCC1CC(Oc1nc(-c3ccc(NC(=O)Nc4ccc(C(N)=O)cc4)cc3)nc(N3CCOCC3)n1)C2
Reaction time: 0.25 h
Yield: 18.8 %

Procedure:
To a stirred solution of triphosgene (120 mg, 0.40 mmol) in CH2Cl2 (3 mL) was added 4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine (200 mg, 0.5 mmol) at 25° C. The reaction mixture was stirred for 15 min and 4-aminobenzamide (204 mg, 1.5 mmol) and NEt3 (692 μL, 5 mmol) were added and the reaction mixture was stirred for additional 1 hr. The solvents were removed and the crude mixture was purified by semi-prep-HPLC (NH3-method) to give 4-(3-{4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-ureido)-benzamide (42 mg, 15% yield) MS (ESI) m/z 559.
Reaction SMILES: [Cl:1][C:2]1[C:7](OC2C=CC=CC=2)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>O1CCOCC1>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:4][CH:5]=[C:6]([N+:15]([O-:17])=[O:16])[C:7]=1[NH:31][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([C:26]([F:25])([F:35])[F:36])[CH:28]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)c(Cl)c1Oc1ccccc1
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)c(Cl)c1NCc1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A mixture of 3.41 gm of 2-chloro-4-nitro-1,3-diphenoxy-benzene, 5 ml of dioxane and 4 gm of 3-trifluoromethyl-benzylamine was stirred for 12 hours at 100° C. Thereafter, the reaction mixture was evaporated, the residue was taken up in chloroform, the resulting solution was extracted first with 2 N sodium hydroxide and then with 2 N hydrochloric acid, and the organic phase was dried with sodium sulfate. The chloroform was distilled off, leaving 4.0 gm (95% of theory) of the title compound as a viscous yellow oil.