Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:13]1([C:11]2[S:12][C:8]([CH2:7][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:9]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)c1nc(-c2ccccc2)sc1CBr
Reactant: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1nc(-c2ccccc2)sc1CN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Pyrrolidine (0.5 ml) was added to a solution of tert-butyl 5-(bromomethyl)-2-phenylthiazole-4-carboxylate (1.029 g, 2.90 mmol) and diisopropylethylamine (DIPEA) (1.5 ml) in CH2Cl2 (10 ml). The mixture was stirred at rt for 30 min, concentrated in vacuo and purified by flash chromatography to give tert-butyl 2-phenyl-5-(pyrrolidin-1-ylmethyl)thiazole-4-carboxylate as a yellow solid (920 mg, 98% yield).
Reaction SMILES: [F-:1].[Cs+].Cl[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8].O>S1(CCCC1)(=O)=O>[F:1][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8]
Reactant: [F-]
Reactant: N#Cc1ccnc(Cl)c1
Agent: [Cs+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: N#Cc1ccnc(F)c1
Temperature: 100 °C
Yield: 89345.7 %

Procedure:
Cesium fluoride (30 g, 0.22 mmol) was slurried in dry sulfolane (150 mL) and concentrated via vacuum distillation at 0.5 mm Hg. After removal of 20% of the solvent, the suspension was cooled and 2-chloroisonicotinonitrile (15 g, 0.11 mmol) was added, then stirred and heated at 100° C. for 20 h. It was cooled to 25° C., poured into H2O (200 mL) and extracted with Et2O. The Et2O phase was washed with H2O, then brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography over SiO2 with CH2Cl2 to give 2-fluoroisonicotinonitrile (12.0 g) as a low-melting colorless solid: EIMS m/z: 122 ([M]+); 1H NMR (CDCl3): δ 8.45 (dd, 1H), 7.47 (dd, 1H), 7.24 (m, 1H).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:31]=[CH:30][CH:29]=[CH:28][C:7]=1[CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>CS(C)=O>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH2:14][O:13][C:12]1[CH:11]=[C:10]([CH:27]=[CH:26][CH:25]=1)[O:9][CH2:8][C:7]1[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=1[CH2:5][C:1]#[N:2]
Reactant: ClCc1ccccc1COc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccccc1COc1cccc(OCc2ccc3ccccc3n2)c1
Reaction time: 5 h

Procedure:
Sodium cyanide (14 mg, 0.28 mmol) is added to a solution of 2-[3-(2-chloromethyl-benzyloxy)-phenoxymethyl]-quinoline (110 mg, 0.28 mmol, example 37) in DMSO (5 mL) and the reaction is stirred 5 h. The reaction is partitioned between water and ethyl acetate, the organic phase is washed with water, dried and concentrated to provide the title compound which is used without further purification. MS (ESI) 381 (M+H)+.
Reaction SMILES: CN([CH:4]=[O:5])C.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]([NH2:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=1>O>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:19][C:4]2=[O:5])[CH:7]=1
Reactant: CN(C)C=O
Reactant: Nc1ccccc1Nc1cccnc1
Solvent: O
Product: O=c1[nH]c2ccccc2n1-c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N,N′-Carbonyldiimidazole(0.57 g) was added to a DMF solution (5 ml) of N-pyridine-3-ylbenzene-1,2-diamine(0.5 g). The mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and the precipitated insoluble matter was separated, washed with water, and dried to give the title compound(0.5 g) as a pale whitish purple powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[I:9].[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC1C=CC=CC=1>[Br:10][CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([I:9])[CH:4]=1
Reactant: Cc1cnc(Cl)c(I)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: Clc1ncc(CBr)cc1I
Yield: 64 %

Procedure:
4.60 g (18.15 mmol) of 6-chloro-5-iodo-3-methylpyridine (Setliff et al., J. Chem. Engineering Data (1976), 21(2), 246-7), 3.39 g (19.06 mmol) of N-bromosuccinimide and 0.30 g (1.82 mmol) of 2,2′-azobis(2-methylpropionitrile) in 500 ml of chlorobenzene are boiled under reflux for about 16 hours. The reaction mixture is washed with saturated aqueous sodium sulphite solution and sodium bicarbonate solution and then dried over sodium sulphate and concentrated under reduced pressure. Column cluomatography of the residue on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (1:10) gives 3.86 g (38% of theory) of 3-bromomethyl-6-chloro-5-iodopyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH:7]([CH3:9])[CH2:6][NH:5]1.C(=O)([O-])O.[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH:7]([CH3:9])[CH2:6][N:5]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CC(C)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CC(C)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
(2S)-4-Methylproline methyl ester (0.93 g (6.5 mmol), prepared as described in 2)) was dissolved in toluene (20 ml). To the solution were added an aqueous solution (20 ml) of sodium hydrogencarbonate (1.89 g, 22.5 mmol) and benzyl chloroformate (1.54 ml, 10.8 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and the solvent was removed by distillation under reduced pressure, to give (2S)-1-benzyloxycarbonyl-4-methylproline methyl ester (1.78 g) as a pale yellow oil (yield 99%). All of the compound obtained above was dissolved in tetrahydrofuran (30 ml). To the resulting solution was added lithium borohydride (0.28 g, 13 mmol) in three portions, and the resulting mixture was stirred at room temperature. Ice was added to the mixture and the mixture was stirred for 1 hour. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, ethyl acetate:hexane=2:5), to give the title compound (1.07 g) as a pale yellow oil (yield 66%).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:13][CH2:12]1.[CH2:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH2:30][CH2:29][NH:28][CH2:27]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:30]1[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:26][CH2:27][N:28]([C:23]([C:19]2[N:20]=[CH:21][N:22]=[C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:16][CH2:15]3)[CH:18]=2)=[O:24])[CH2:29]1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: c1ccc2c(c1)CCNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2ccccc2CC1

Procedure:
100.0 mg (0.29 mmol) 6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 50.0 mg (0.34 mmol) 2,3,4,5-tetrahydro-1H-3-benzazepine, 100 μL (0.71 mmol) triethylamine and 100.0 mg (0.31 mmol) TBTU in 1.5 mL DMF were stirred overnight at RT. The reaction mixture was filtered through a syringe filter and the solution was purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][C:2]1=[O:8].[CH2:9]([O:16][CH2:17]Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:9]([O:16][CH2:17][N:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][C:2]1=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: ClCOCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: ClCCl
Product: O=c1ccn(COCc2ccccc2)c(=O)[nH]1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
After N,O-bis(trimethylsilyl)acetoamide (18.5 ml, 74.8 mmol) was added dropwise to a suspension of pyrimidine-2,4-dione (3.36 g, 30.0 mmol) in dichloromethane (90 ml) at room temperature, the mixture was stirred for 2 hours. Tetra-n-butyl ammonium iodide (1.12 g, 3.0 mmol) was added to the reaction mixture, and benzyloxymethyl chloride (4.4 ml, 31.7 mmol) was further added to it. This mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with water and a saturated aqueous solution of sodium hydrogencarbonate, and it was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium thiosulfate and with water successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solid residue was washed with diisopropyl ether and collected by filtration to give the title compound (6.00 g, yield 86%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[CH3:17][C:18]1[S:22][C:21](/[CH:23]=[CH:24]/[C:25](Cl)=O)=[CH:20][CH:19]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53]>C(OCC)(=O)C>[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53].[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:25](/[CH:24]=[CH:23]/[C:21]3[S:22][C:18]([CH3:17])=[CH:19][CH:20]=3)=[N:16][C:5]=2[CH:4]=1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Reactant: Cc1ccc(/C=C/C(=O)Cl)s1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/c1ccc(C)s1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy -2-amino-N-(2-pyridyl)aniline and (E)-3-(5-methyl-2-thienyl)acryloyl chloride (Sekiya, T.; Hiranuma, H.; Hata, S.; Mizogami, S.; Hanazuka, M.; Yamada, S. J. Med. Chem., 1983, 26, 411) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from MeOH/n-hexane yielded the titled compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[I-].[K+].[CH2:31]([NH:34][CH2:35][CH:36]=[CH2:37])[CH:32]=[CH2:33]>O1CCCC1>[CH2:31]([N:34]([CH2:35][CH:36]=[CH2:37])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][N:34]([CH2:35][CH:36]=[CH2:37])[CH2:31][CH:32]=[CH2:33])=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7])[CH:32]=[CH2:33]
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1S2
Reactant: C=CCNCC=C
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCN(CC=C)CCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCCN(CC=C)CC=C)ccc1S2
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A mixture of 22.3 g (0.05 mole) of 2,7-bis(5-chlorovaleryl)thioxanthene, 1 g of potassium iodide, 100 ml of diallylamine and 200 ml of tetrahydrofuran is placed in a Paar bomb and heated to 120°C with stirring for 24 hours. Upon cooling, the mixture is filtered and the filtrate evaporated to dryness. The resulting residue is dissolved in dilute HCl and extracted with ether. The aqueous portion is made basic, extracted with methylene chloride, dried over magnesium sulfate and filtered. The filtrate is heated to boiling, treated with charcoal, filtered and filtrate evaporated to dryness. The residue is chromatographed on a column of alumina and eluted with methylene chloride. The resulting oil is dissolved in diethyl ether, dried over molecular sieves, filtered and the ether evaporated. This process is repeated several times to yield 2,7-bis(5-diallylaminovaleryl)thioxanthene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH:22]1([C:26]2[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][N:27]=2)[CH2:25][CH2:24][CH2:23]1.[S].C(O)(=O)C>C(O)C>[CH:22]1([C:26]2[N:31]=[C:30]([C:32]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]6[CH2:21][CH2:20][CH2:19][CH2:18]6)=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH:29]=[CH:28][N:27]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: O=Cc1ccnc(C2CCC2)n1
Agent: [S]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CCC5)n4)[nH]c3n2)C1)N1CCCC1
Reaction time: 16 h

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (135.9 mg, 0.5 mmol) in ethanol was added 2-cyclobutylpyrimidine-4-carbaldehyde (76.2 mg, 0.5 mmol), sulfur (30.1 mg, 0.9 mmol) and acetic acid (0.15 mL) at room temperature under nitrogen. The reaction mixture was stirred for 16 h at reflux. The solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via preparative TLC to afford the title compound as a yellow solid. MS (ES+APCI) (M+H) 432.1; LCMS retention time 2.567 min (Method G).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@@H:11]([N:13]5[CH2:14][CH2:18][CH2:15][CH2:16][CH2:17]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:25][N:24]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: COc1ncc(B(O)O)cn1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@@H](N5CCCCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 32A for the product of Example 1E, and substituting 2-methoxypyrimidine-5-boronic acid for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.77 (s, 2H) 8.04 (d, J=8.42 Hz, 1H) 7.98 (s, 1H) 7.58 (dd, J=8.42, 1.87 Hz, 1H) 4.08 (s, 3H) 3.55-3.68 (m, 1H) 2.79-2.91 (m, 1H) 2.66-2.77 (m, 2H) 2.23-2.49 (m, 6H) 1.52-1.73 (m, 6H). MS: (M+H)+=381.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1.[C:14]([CH2:16]CSSCCC#N)#[N:15].IC1C(C2C=NC=CC=2)=NNC=1>C(OCC)(=O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:4]2[C:3]([S:2][CH2:1][CH2:16][C:14]#[N:15])=[CH:7][NH:6][N:5]=2)[CH:9]=1
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: N#CCCSSCCC#N
Agent: Ic1c[nH]nc1-c1cccnc1
Solvent: CCOC(C)=O
Product: N#CCCSc1c[nH]nc1-c1cccnc1
Yield: 62 %

Procedure:
Compound 21R was prepared following the procedure as described for the synthesis of compound 21A (see Scheme 3) using 3-(2-cyano-ethyldisulfanyl)-propionitrile as the disulfide and 3-(4-iodo-1H-pyrazol-3-yl)-pyridine (compound 20B). (conditions flash chromatography (ethyl acetate)) Yield: 62%. (oil). 1H-NMR (200 MHz, CDCl3): δ 9.20 (d, J=2 Hz, 1H), 8.60 (dd, J=5 Hz, 2 Hz, 1H), 8.33 (dt, J=8 Hz, 2 Hz, 1H), 7.82 (s, 1H), 7.43-7.37 (m, 1H), 2.76 (t, J=7 Hz, 2H), 2.45 (t, J=7 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].[C:29]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])[NH:30][NH2:31].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:31][NH:30][C:29]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:23]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)O)nc2ccc(F)cn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)NNC(=O)OC(C)(C)C)nc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 57 %

Procedure:
2.2 250 mg (0.666 mmol) of 2-[3-(2,6-dimethylphenylamino)-6-fluoroimidazo[1,2-a]pyridin-2-yl]benzoic acid, 88 mg (0.666 mmol) of tert-butyl carbazate, 153 mg (0.800 mmol) of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (DAPECI) are dissolved in 1 ml of DMF and stirred at RT for 5 hours. The mixture is subsequently added to water, the precipitated solid is filtered off with suction and dried, giving 187 mg (57%) of tert-butyl N′-{2-[3-(2,6-dimethylphenylamino)-6-fluoroimidazo[1,2-a]-pyridin-2-yl]benzoyl}hydrazinecarboxylate as solid; MS-FAB (M+H+)=490.8; Rf (HPLC, polar method): 1.47 min. This is employed in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.[NH2:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23].C(O)C>C(O)(=O)C>[CH3:26][C:20]1[NH:19][C:10]([CH3:11])=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)C(=Cc1ccc(F)cc1)c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)NC(C)=C(c2ccccc2)C1c1ccc(F)cc1
Yield: 111.1 %

Procedure:
24.0 g (0.1 mol) of 1-(4-fluorophenyl)-2-phenylbuten-3-one, 23 g (0.2 mol) of methyl 3-amino-crotonate and 6 ml (0.1 mol) of glacial acetic acid are heated under reflux overnight in 1 50 m of ethanol, heated under reflux for 18 h after addition of 11.5 g (0.1 mol) of methyl 3-aminocrotonate and 3ml of glacial acetic acid and heated under reflux for 18 h once more after repeated addition of 11.5 g (0.1 mol) of methyl 3-aminocrotonate and 3 ml of glacial acetic acid. The solvent is removed in vacuo, 80 ml of methanol are added to the residue, undissolved material is filtered off with suction, the methanolic solution is concentrated in vacuo and excess aminocrotonate is distilled off from the residue at 73° C.-90° C./18 mbar and subsequently at 60° C.-70° C. 0.2 mbar. 37.5 g of crude product are obtained as a brittle fused mass.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[F:17])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:18]([OH:28])(=[O:27])[C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:20].O>C(O)(C)C>[C:18]([OH:28])(=[O:27])[C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:20].[NH2:1][C@H:2]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[F:17])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(N)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: O
Solvent: CC(C)O
Product: COC(=O)C[C@H](N)Cc1cc(F)c(F)cc1F
Temperature: 77.5 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
The methyl(3RS)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (260 gm, 1.05 mol) (29) was charged in isopropanol (6.0 vol, 1.56 Ltr) at 25-30° C. and the reaction mixture was stirred for 15 minutes to give a clear solution. After 15 minutes stirring, controlled addition of a solution of (R)-(−)-mandelic acid [2.0 eq, 320 gm in 6.0 vol, 1.56 Ltr of isopropanol] was carried out. After completion of the addition, the reaction mixture was stirred at 25-30° C. for 3 hours to give enantiomerically enriched crude methyl(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (R)-(−)-mandelate as a white coloured product. The product was filtered, washed with isopropanol (1.0 vol, 260 ml), and dried in a vacuum oven at 40-45° C. for 4-5 hours to give enantiomerically enriched crude methyl(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (R)-(−)-mandelate (135 gm, molar yield: 64%). The dried enantiomerically enriched crude methyl(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (R)-(−)-mandelate product (135 gm) was charged in isopropanol (20.0 vol, 2.7 Ltr) at 25-30° C. and the white suspension was further heated at 75-80° C. for 0.5 hour to give a partially clear solution. The partially clear solution was made clear by the addition of water (2.0 vol, 270.0 ml) at 75-80° C. The clear solution was further stirred for 0.5 hour. After stirring for 0.5 hour, the clear solution was gradually cooled to 0-5° C. within 3 hours to give enantiomerically enriched pure methyl(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (R)-(−)-mandelate (30) as white coloured product. The product was filtered, washed with isopropanol (1.0 vol, 135.0 ml), and dried in a vacuum oven at 40-45° C. for 4-5 hours.
Reaction SMILES: [C:1]([O:9]C)(=O)/[CH:2]=[CH:3]\[C:4](OC)=[O:5].[CH2:11]([NH2:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>C1(C)C=CC=CC=1>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:18][C:1](=[O:9])[CH:2]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH2:18])[CH2:3][C:4]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH2:18])=[O:5]
Reactant: COC(=O)/C=C\C(=O)OC
Reactant: NCCCCCCN
Solvent: Cc1ccccc1
Product: NCCCCCCNC(=O)CC(NCCCCCCN)C(=O)NCCCCCCN

Procedure:
Dimethyl maleate (72 g, 0.5 moles) is added over a 2-3 hour period to a solution of 1,6-hexanediamine (174 g, 1.5 moles) in toluene (360 g) at 75°-80° C. The reaction temperature rises from 80° to 110° C. under reflux conditions. After the addition is completed, methanol is distilled at a reaction temperature of 120°-125° C. Additional toluene (320 g) is added to maintain reaction volume. The reaction may be followed by amine titration or by disappearance of the methyl ester in the 1H NMR spectrum. After the reaction is complete, toluene is removed under vacuum (50°-70° C., 15-20 mm Hg) to give N,N'-bis(6-aminohexyl)-2-[(6-aminohexyl)amino]butanediamide as a viscous liquid which solidifies on standing.
Reaction SMILES: I[C@@:2]1([N:11]2[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]2=[O:13])[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5](O)[C@H:3]1O.[CH2:19]([NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[C:20]#[CH:21].CO>ClCCl>[F:25][C:24]([F:27])([F:26])[C:23]([NH:22][CH2:19][C:20]#[C:21][C:17]1[C:15](=[O:16])[NH:14][C:12](=[O:13])[N:11]([CH:18]=1)[C@@H:2]1[O:10][C@H:7]([CH2:8][OH:9])[CH2:5][CH2:3]1)=[O:28]
Reactant: O=c1ccn([C@]2(I)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: C#CCNC(=O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(NCC#Cc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F

Procedure:
Iodouridine 21 was coupled for 3 hours to N-propargyltrifluoroacetamide following the general method given in Example 5C. Chromatography with a 0-5% methanol in dichloromethane gradient afforded material which was homogeneous by TLC, but which was difficult to dry. After co-evaporating the chromatographed product several times with chloroform and vacuum-drying, 536.5 mg of alkynylamino nucleoside 22 was obtained as a white foam. This material was homogeneous by TLC and was pure by NMR except for a small amount (39 mole %; corrected yield 66%) of chloroform.