Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]#[CH:12])=[CH:4][N:3]=1.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]#[C:12][C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:23])([F:22])[F:13])=[CH:16][CH:17]=2)=[CH:4][N:3]=1
Reactant: C#Cc1cnc(N)c(C#N)c1C
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C#Cc2ccc(C(F)(F)F)cc2)cnc(N)c1C#N

Procedure:
A solution of 1.6 grams (0.010 mole) of 2-amino-3-cyano-4-methyl-5-ethynylpyridine, 3.8 grams (0.014 mole) of 4-trifluoromethylphenyl iodide (commercially available), 3.5 grams (0.035 mole) of triethylamine, 0.3 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.3 gram (catalyst) of copper(I)iodide in 75 mL of acetonitrile is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is concentrated under reduced pressure to a residue. The residue is partitioned between ethyl acetate and aqueous 1N hydrochloric acid. The aqueous layer and the organic layer are separated, and the aqueous layer is washed with ethyl acetate. The ethyl acetate wash is combined with the organic layer, and the combination is washed with an aqueous solution of 10% lithium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2-amino-3-cyano-4-methyl-5-[(4-trifluoromethylphenyl)ethynyl]pyridine.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[CH:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[C:14]1=[O:23])[CH2:20]2.Cl>C1COCC1>[CH2:6]([C:7]1[CH:8]=[C:9]([C:14]2([OH:23])[CH:15]3[CH2:21][CH:19]4[CH2:18][CH:17]([CH2:22][CH:13]2[CH2:20]4)[CH2:16]3)[CH:10]=[CH:11][CH:12]=1)[CH3:5]
Reactant: BrCCc1ccccc1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1cccc(C2(O)C3CC4CC(C3)CC2C4)c1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A stirring mixture of magnesium turnings (0.89 g, 36.6 mmol) and iodine (catalytic) in dry THF (60 mL) was treated with 3-bromoethylbenzene (5 mL, 36.6 mmol), refluxed for 3 h, cooled to room temperature, treated with a solution of 2-adamantanone (5.0 g, 33.3 mmol) in dry THF (20 mL) and refluxed for 2 h. The mixture was cooled to room temperature, treated with 3-M HCl (20 mL), extracted with EtOAc (2×20 mL), the combined extracts were washed with water (10 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; heptane-EtOAc (9:1)] to give the product (7.84 g, 92 %) as a white solid: mp 63-65° C.; IR νmax (Nujol)/cm−1 3442, 3281, 2921, 2855, 1604, 1451, 1101, 1043, 1009, 803 and 708; NMR δH (400 MHz, CDCl3) 1.23 (3H, t, J 7.5 Hz), 1.61-1.70 (9H, m), 1.89 (1H, s), 2.38-2.41 (2H, m), 2.56 (2H, s), 2.65 (2H, q, J 7.5 Hz), 3.46 (1H, s), 7.11 (1H, d, J 7.5 Hz) and 7.24-7.36 (3H, m); Anal. Calcd for C18H24O: C, 84.32; H, 9.43. Found: C, 84.24; H, 9.28.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].CCN(CC)CC.[OH:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:20]=[C:19]([CH3:21])[S:18][C:17]=2[CH:22]=1>C1COCC1.CCOC(C)=O>[C:1]([O:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:20]=[C:19]([CH3:21])[S:18][C:17]=2[CH:22]=1)(=[O:3])[CH3:2]
Reactant: Cc1cc2ccc(O)cc2s1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2cc(C)sc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 126.1 %

Procedure:
Acetyl chloride (1.5 ml, 1.66 g, 21 mmole) and Et3N (3 ml, 2.18 g, 21.5 mmole) were added, sequentially, to a solution of 6-hydroxy-2-methylbenzo[b]thiophene 8a (2.51 g, 15 mmole) in THF (120 ml) at 0°. The reaction was left stirring for 14 hours, gradually warming to ambient temperature, then diluted with EtOAc (100 ml) and washed with H2O (100 ml) and brine (100 ml). The combined aqueous layers were extracted with EtOAc (100 ml). The combined organic extracts were subsequently dried over Na2SO4 and concentrated, in vacuo, to give 3.9 g of a yellow solid which was purified by silica gel chromatography. Elution with hexane: Et2O (90:10) and evaporation of the appropriate fractions gave 2.93 g (93%) of a white solid. 1H NMR (DMSO-d6) δ 7.70 (1H, d, J=8.6 Hz), 7.66 (1H, d, J=2.2 Hz), 7.12 (1H, s), 7.07 (1H, dd, J=2.2, 8.6 Hz), 2.54 (3H, s), 2.27 (3H, s). Anal. Calcd. for C, 11H10O2S: C, 64.05; H, 4.89; S, 15.55. Found: C, 63.84; H, 4.93; S, 15.57.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].C(O)(=O)C.C(O)(C(F)(F)F)=O.[Br:25]Br>O>[Br:25][C:13]1[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[NH:11][C:10](=[O:12])[O:9][C:7](=[O:8])[C:6]=12
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2[nH]c(=O)oc(=O)c2c1Br
Temperature: 5 °C

Procedure:
To a suspension of 5-methyl-isatoic anhydride (9.2 g, 0.052 mol) in a mixture of glacial acetic acid (60 mL) and TFA (30 mL), bromine (9.9 g, 0.062 mol) was added under stirring at 5° C. Reaction mixture warmed to room temperature and stirred˜5 hours. Poured in cold water and yellow ppt filtered and washed with water and dried. Yield: 12.09 g, 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH2:17])[N:8]=[C:9](N3C=NC=N3)[C:10]=2[N:11]=1.[CH2:18]([Mg]Br)[CH2:19][CH3:20]>O1CCCC1.CN1CCCC1=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH2:17])[N:8]=[C:9]([CH2:18][CH2:19][CH3:20])[C:10]=2[N:11]=1
Reactant: CCC[Mg]Br
Reactant: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCCc1nc(N)nc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of the intermediate of example 1 (0.47 g, 1.9 mmol) and iron tris(acetylacetonate) (34 mg, 0.095 mmol) in tetrahydrofuran (50 ml, hereinafter THF) and N-methylpyrrolidone (20 ml, hereinafter NMP) was added n-propylmagnesium bromide (1.9 ml, 3.8 mmol as a 2.0 M solution in THF). After stirring at room temperature for 40 minutes, the solution was diluted with THF and then quenched by adding a solution of 1N HCl. The mixture was extracted with ethyl acetate (150 ml), then dried over Na2SO4 and concentrated to afford 6-chloro-4-n-propyl-pyrido[3,2-d]pyrimidin-2-ylamine as a brown solid (0.32 g), which was used in the next step without purification. Its mass spectrum data was as follows: MS (m/z) 223.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]1([O:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:14]2[CH:15]=[CH:16][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(Br)cc2)cc1
Yield: 100.9 %

Procedure:
To a cooled (ice bath, 5° C.) mixture of 4-bromobenzoyl chloride (25.0 g, 0.114 mol) and anisole (15.5 g, 0.143 mol, 1.25 eq) in CH2Cl2 (500 mL) was added AlCl3 (19.0 g, 0.143 mol, 1.25 eq) portion-wise over a period of 20 minutes with stirring under a nitrogen atmosphere. The resulting reaction mixture was allowed to stir between 5° C. and 20° C. for 3 h. The reaction mixture was poured slowly into 20% aqueous HCl (500 mL), stirred for 15 min, and layers were separated. The aqueous layer was further extracted with CH2Cl2 (3×250 mL). The combined organic layer washed with water (200 mL), brine (200 mL) dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 33.48 g (100%) of compound 1 as a white solid. 1H NMR (300 MHz, CDCl3): δ 3.91 (s, 3 H), 6.99 (d, J=8.7 Hz, 2 H), 7.65 (s, 4 H), 7.82 (d, J=8.7 Hz, 2 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])=[N:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([O:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][N:14]=2)=[N:7][CH:6]=1
Reactant: Oc1ccccc1Oc1ccc(Cl)cn1
Reactant: Clc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Clc1ccc(Oc2ccccc2Oc2ncc(Cl)cn2)nc1
Yield: 76.5 %

Procedure:
With stirring, 1.80 grams (0.012 mole) of 2,5-dichloropyrimidine was added to a mixture of 2.0 grams (0.009 mole) 2-(5-chloropyridin-2-yloxy)phenol, 1.5 grams potassium carbonate, and 40 ml of methyl ethyl ketone. After the addition, the mixture was heated at reflux overnight and then poured into excess H2O. After extracting with 200 ml of ethyl ether, the extract was washed with saturated NaHCO3, H2O, brine, dried (MgSO4), filtered, and evaporated to yield a yellow solid which was recrystallized from 1-chlorobutane to give 2.3 grams of product, m.p. 108°-111°; ir (Nujol): 6.35, 6.50 (C=N), 13.20 microns; NMR (CDCl3): δ6.75 (d, 1H, pyridine ring proton), 7.35 (s, 4H, ArH), 7.65 (AB quartet, 1H, pyridine ring proton), 8.10 (d, 1H, pyridine ring proton), 8.55 (s, 2H, pyrimidine ring protons).
Reaction SMILES: CS(O)(=O)=O.[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]([NH2:13])=[NH:12].[Cl:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25][C:26]([CH3:28])=O.C([O-])(=O)C.[Na+]>C(O)C>[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]1[NH:13][C:26]([CH3:28])=[C:25]([C:24]([O:30][CH2:31][CH3:32])=[O:29])[CH:17]([C:16]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:15]=2[Cl:14])[N:12]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)c1ncc[nH]1
Reactant: O=Cc1ccc(F)cc1Cl
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(c2ncc[nH]2)=NC1c1ccc(F)cc1Cl
Yield: 26.2 %

Procedure:
2 mmol 1H-imidazol-2-formamidine methane sulfonate (Tommasi, R. A., Macchia, W. M., Parker, D. T., Tetrahedron Lett 1998, 39:5947-5950), 2 mmol 2-chloro-4-fluorobenzaldehyde, 2 mmol ethyl acetoacetate and 2.2 mmol sodium acetate were reacted under reflux in 10 ml anhydrous ethanol for 20 hr, concentrated, and then ethyl acetate and water were added to separate the layers. The ethyl acetate layer was dried over anhydrous sodium sulfate, and separated by a column chromatography to obtain 0.19 g of a colorless fine needle crystal with mp 157-162° C.; 1H-NMR (400 MHz, DMSO-d6) δ 1.02-1.06 (3H, t, J=7 Hz); 2.43 (3H, s); 3.91-3.93 (2H, m, J=7 Hz); 5.99 (1H, s); 7.04-7.42 (5H, m); 9.59 (1H, s); 12.69 (1H, s); MS (EI) 362.1 (M+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:19])[NH:5][C:6](C)([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[CH:7]=1.[NH2:20][C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23].[CH3:26]S(C)=O>>[CH3:19][C:4]1[N:3]=[C:2]([NH:20][C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])[C:7]([CH3:26])=[C:6]([O:8][C:9]2[C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[CH:13][C:14]=2[CH3:15])[N:5]=1
Reactant: CC1=NC(Cl)=CC(C)(Oc2c(C)cc(C)cc2C)N1
Reactant: CS(C)=O
Reactant: CC[C@H](N)CO
Product: CC[C@@H](CO)Nc1nc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 130 °C

Procedure:
A mixture of 4-chloro-2,6-dimethyl-6-(2,4,6-trimethylphenyoxy)-pyrimidine (30 mg) and 2-(S)-amino-1-butanol (0.5 ml) in 0.5 ml of DMSO was heated at 130° C. for 4 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a crude material. The crude residue was purified through silica gel column chromatography to give 24 mg of the title compound as white crystals. High MS for (C19H27N3O2) calc. 329.2103, found 329.21249; IR(KBr) 3400, 2940,1580 cm-1 ; 1H NMR (CDCl3) δ6.841 (s, 2H), 5.72 (brs, 1H), 4.45 (d, 1H), 3.82-3.96 (m, 1H), 3.72-3.9 (m, 1H), 3.5-3.6 (m, 1H), 2.27 (s, 3H), 2.21 (s, 3H), 2.08 (s, 3H), 2.02 (s, 6H), 1.4-1.7 (m, 2H), 1.03 (t, 3H) ppm.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2[CH:18]=[C:17]([NH:19][C:20]3[C:25]([CH3:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=3)[CH:16]=[CH:15][C:14]=2[NH2:28])[CH:8]=[CH:9][CH:10]=1.Cl.O.[OH-].[Na+]>COCCO.O1CCOCC1>[CH3:26][C:25]1[CH:24]=[N:23][C:22]2[NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([CH:6]=3)[CH2:11][CH2:12][C:13]3[CH:18]=[C:17]([NH:19][C:20]=1[N:21]=2)[CH:16]=[CH:15][C:14]=3[NH2:28]
Reactant: Cc1cnc(Cl)nc1Nc1ccc(N)c(CCc2cccc(N)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: COCCO
Product: Cc1cnc2nc1Nc1ccc(N)c(c1)CCc1cccc(c1)N2
Yield: 42 %

Procedure:
To a solution of 2-[2-(3-aminophenyl)ethyl]-N(4)-(2-chloro-5-methylpyrimidin-4-yl)benzene-1,4-diamine trihydrochloride (0.16 g, 0.45 mmol) in 2-methoxyethanol (2 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (110 μL). The resultant mixture was heated at 150° C. in the microwave for 15 min. After cooling, water and NaOH (12 N) were added to neutralize the mixture to pH=7. The aqueous layer was extracted with EtOAc four times. The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel column chromatography to give the desired product as an off-white powder (60 mg, 48%). LCMS for C19H20N5 (M+H)+: m/z=318.2.
Reaction SMILES: [CH:1]1([C:4]2[CH:17]=[CH:16][C:7]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[OH:15])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C(P(CCCC)CCCC)CCC.[CH2:31]([O:38][C@H:39]1[C@H:44]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:43]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@@H:42](O)[CH:41]=[C:40]1[CH2:62][O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C(/N=N/C(N(C)C)=O)=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH:1]1([C:4]2[CH:17]=[CH:16][C:7]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C@H:42]3[C@H:43]([O:53][CH2:54][C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[C@@H:44]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C@H:39]([O:38][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:40]([CH2:62][O:63][CH2:64][C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)=[CH:41]3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: Oc1ccccc1Cc1ccc(C2CC2)cc1
Reactant: O[C@H]1C=C(COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C1=C(COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1Oc1ccccc1Cc1ccc(C2CC2)cc1
Reaction time: 20 h
Yield: 62 %

Procedure:
In a nitrogen stream, 2-(4-cyclopropylbenzyl)phenol and tributylphosphine (70 μL, 0.28 mmol) were added to a solution of (1S,4R,5S,6S)-4,5,6-tris(benzyloxy)-3-(benzyloxymethyl)cyclohex-2-enol (51 mg, 0.095 mmol) as described in a document [J. Org. Chem., 63, 5668-5671 (1998)] in toluene (300 μL) under cooling with ice, and then tetramethylazodicarboxamide (48 mg, 0.28 mmol) was added thereto at the same temperature. The reaction mixture was stirred at the same temperature for 20 hours and then hexane was added thereto and the precipitate was filtered and the solvent of the filtrate was distilled. The obtained residue was purified by preparative TLC [developing solution=ethyl acetate:n-hexane (1:5) to obtain the title compound (44 mg, 62%).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[C:22]([CH3:26])[C:23]([CH3:25])=[CH:24][C:18]=2[N:17]=1)=[N+:13]=[N-:14]>>[ClH:1].[ClH:1].[CH3:25][C:23]1[C:22]([CH3:26])=[CH:21][C:19]2[NH:20][C:16]([CH2:15][N:12]3[CH:5]=[C:4]([CH2:3][CH2:2][C:6]4[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=4)[N:14]=[N:13]3)=[N:17][C:18]=2[CH:24]=1
Reactant: Cc1cc2nc(CN=[N+]=[N-])[nH]c2cc1C
Reactant: C#CCCc1c[nH]c(N)n1
Agent: Cl
Product: Cc1cc2nc(Cn3cc(CCc4c[nH]c(N)n4)nn3)[nH]c2cc1C
Yield: 117.6 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.0734 g, 0.432 mmol) was reacted with 2-azidomethyl-5,6-dimethyl-1H-benzimidazole (0.104 g, 0.518 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(5,6-Dimethyl-1Hbenzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine dihydrochloride (0.104 g, 59%) of a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.70 (s, 1H), δ 7.19 (s, 2H), δ 6.23 (s, 1H), δ 5.66 (s, 2H), δ 2.85 (t, 2H), δ 2.68 (t, 2H), □ 2.21 (s, 6H) ppm; 13C (75 MHz, CD3OD) δ 148.2, 147.0, 146.9, 132.3, 128.9, 122.8, 120.0, 115.1, 109.7, 100.4, 25.1, 24.4, 19.2 ppm; HRMS (ESI) calcd for C17H20N8 (M+) 337.1883. found 337.1886.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1ccccc1-c1ccc(F)cc1

Procedure:
Chlorosulfonic acid (8.7 mL, 0.13 mole) was added dropwise to stirred cold (0° C.) 4-fluorobiphenyl (10.2 g, 59 mmol). After 30 minutes at 0° C. the reaction mixture was poured onto ice. The resulting white precipitate was collected by filtration and dissolved in chloroform. The chloroform solution was washed with water, brine, dried over magnesium sulfate, and concentrated to afford a white solid. The desired 4′-fluorobiphenylsulfonyl chloride (4.3 g), was separated from 4′-fluorobiphenylsulfonic acid by crystallization of the latter from ethyl acetate and crystallization of the remaining material from hexanes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[CH:27][C:26]=1[F:36].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.C(N(CC)CC)C>C(Cl)(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH2:10][C@@H:9]1[C:21](=[O:22])[NH:24][C:25]1[CH:35]=[CH:34][C:28]([C:29](=[O:30])[N:31]([CH3:32])[CH3:33])=[CH:27][C:26]=1[F:36])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)O
Reactant: CN(C)C(=O)c1ccc(N)c(F)c1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(NC(=O)[C@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Yield: 17.9 %

Procedure:
Into a solution of 2 (1.25 g, 3.61 mmol) in CHCl3 (25 mL) was added 5 (0.66 g, 3.61 mmol), EEDQ (1.07 g, 4.32 mmol), and triethylamine (0.74 mL, 5.33 mmol). The solution was stirred at reflux for 19 h before cooling to RT and adding EtOAc. The solution was washed sequentially with 1N HCl, 0.1N NaOH, water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was purified on a silica gel column eluted with 20% moving to 50% EtOAc in hexanes. Combined and concentrated pure fractions. to give 6 (0.33 g, 18%). MS: APCI (AP+): 510.3 (M)+, (AP−): 508.4 (M)−.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]([C:12](=[O:27])[NH:13][C:14]2[S:15][C:16]([CH2:25]O)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[C:42]([N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>ClCCl>[C:45]([O:44][C:42]([N:49]1[CH2:54][CH2:53][N:52]([CH2:25][C:16]2[S:15][C:14]([NH:13][C:12](=[O:27])[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:29][CH:28]=3)([CH3:11])[CH3:10])=[N:18][C:17]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:51][CH2:50]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccccc2)c(CO)s1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2sc(NC(=O)C(C)(C)NC(=O)c3ccc(F)cc3)nc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-Fluoro-N-[1-(5-hydroxymethyl-4-phenyl-thiazol-2-ylcarbamoyl)-1-methyl-ethyl]-benzamide (82 mg, 0.20 mmol), MsCl (40 uL) and triethylamine (160 uL) in dichloromethane (3 mL) was stirred at RT for 20 min and concentrated. The residue was taken up in MeCN (5 mL), and N-Boc piperazine (120 mg, 0.644 mmol) and triethylamine (160 uL) were added. The mixture was stirred at RT for 20 min and partitioned between ethyl acetate and aq. K2CO3. The combined organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 582.2 (MH+).
Reaction SMILES: [C:1]([N:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[CH3:7])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18].ClC(OCC)=O.[CH2:30]([N:32](CC)CC(N)C)C>C(Cl)(Cl)Cl>[CH2:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH2:21][CH2:30][NH:32][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:6]([C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])[CH3:7])=[CH:16][CH:15]=1)[CH3:18]
Reactant: CCN(CC)CC
Reactant: CCN(CC)CC(C)N
Reactant: CC(C)C(=O)N(C)c1ccc(C(=O)O)cc1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNC(=O)c1ccc(N(C)C(=O)C(C)C)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-(iso-butyryl-N-methylamino)-benzoic acid (0.088 g) and triethylamine (0.041 g) in chloroform (4 ml) was added a solution of ethyl chlorformate (0.049 g) in chloroform (1 ml). The mixture was stirred under an N2 atmosphere at room temperature for 1½ hours and then cooled to 0° C. N,N-Diethyl-propylenediamine (0.051 g) in chloroform (1 ml) was added and the mixture was stirred over night. The mixture were washed with 0.5 M NaOH(aq) and water. Drying and evaporation of the solvent gave a residue, which was chromatographed on a silica gel column first eluted/washed with ethylacetate and then eluted with ethylacetate-methanol-triethylamine (12:4:1) to yield 0.098 g, of the title product.