Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.N([O-])=O.[Na+].[BrH:16]>O.[Cu]Br>[Br:16][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc2nc(Br)sc2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
[(2-(6-Fluorobenzothiazolyl))carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester ##STR36## Slurry 2-amino-6-fluorobenzothiazole (0.255 mol) in water (325 mL), heat to reflux and add 48% hydrobromic acid (130 mL). Maintain at reflux for 20 minutes, cool to 0° C. and add a solution of sodium nitrite (17.56 g, 0.255 mol) in water (90 mL), maintaining a temperature of 0° C. Stir at 0° C. for 15 minutes and add by dropwise addition (while keeping cold) to a rapidly stirring mixture of copper (I) bromide (42.03 g,0.293 mol) in 48% hydrobromic acid (86 mL) and water (225 mL). Stir at room temperature for 20 minutes. Allow to stand overnight, extract into methylene chloride and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give 2-bromo-6-fluorobenzothiazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.I[C:38]1[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: Cc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 3-iodotoluene according to the general procedure C. Obtained as a yellow solid (524 mg).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([O:30]C)[N:24]=2)=[CH:16][C@@H:17]2[NH:21][C:20](=[O:22])[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[CH2:32](I)[CH3:33]>>[Cl:29][C:26]1[C:25](=[O:30])[NH:24][C:23]([CH:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:32][CH3:33])=[CH:14][CH:13]=2)[CH2:16][C@H:17]2[CH2:18][CH2:19][C:20](=[O:22])[NH:21]2)=[CH:28][CH:27]=1
Reactant: CCI
Reactant: COc1nc(C(=C[C@H]2CCC(=O)N2)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)ccc1Cl
Product: CCOc1ccc(C(C[C@H]2CCC(=O)N2)c2ccc(Cl)c(=O)[nH]2)cc1

Procedure:
An (R,S) mixture of the title compound was obtained as a colorless amorphous (240 mg) by performing substantially the same reaction as in Examples 1-16(2)(3) and 4-209 and 4-210(2)(3) sequentially except for using (5R)-5-[2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one obtained in Example 4-48(1) and using ethyl iodide in place of methyl iodide. This was separated by chiral HPLC (CHIRALCEL OD-H, 40° C., flow rate: 7 mL/min, ethanol:hexane=0:100) to give one diastereomer (A) of the title compound as a colorless amorphous (38 mg) and the other diastereomer (B) of the title compound as a colorless amorphous (35 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21](O)=[O:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.O[NH:44][C:45](=[NH:47])[CH3:46]>CC#N.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]=[C:13]([C:18]4[CH:26]=[CH:25][CH:24]=[C:20]([C:21]5[O:22][N:47]=[C:45]([CH3:46])[N:44]=5)[CH:19]=4)[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=N)NO
Reactant: O=C1CC(c2cccc(C(=O)O)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1noc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoic acid (Example 163) (262 mg, 0.7 mmol) and 1-hydroxybenzotriazole (130 mg, 0.84 mmol) in CH3CN/DMF (7 mL/10 mL), cooled to 0° C., was added EDC (161 mg, 0.84 mmol) and the mixture was stirred at 0° C. for 1 h. N-hydroxy-acetamidine (62 mg, 0.84 mmol) was added and stirring was continued for 4 h at 23° C. The reaction mixture was partitioned between ethyl acetate and H2O and the organic layer was dried over Na2SO4 and evaporated in vacuum. The residue was heated in toluene (30 mL) for 20 h at reflux. The mixture was cooled, evaporated in vacuum and the residue was chromatographed on silica gel using ethyl acetate/hexane (2:1) as eluent. The purified product was triturated with ethyl acetate to give the tide compound as light yellow solid (49 mg). MS (ISN) 411.2 [(M−H)−]; mp 266–268° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[NH:4]NC(=O)[C:7]=1[Cl:8].[CH3:11][N:12]([CH:14]=[O:15])C.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCCCCC.O>[CH2:11]([N:12]1[C:14](=[O:15])[C:7]([Cl:8])=[C:2]([Cl:1])[C:3]([O:4][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:10]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1[nH][nH]c(=O)c(Cl)c1Cl
Reactant: BrCc1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Product: O=c1c(Cl)c(Cl)c(OCc2ccccc2)nn1Cc1ccccc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a r.b. flask was added 4,5-dichloro-1,2-dihydropyridazine-3,6-dione (20 gm, 73.8 mmol), DMF (200 ml), potassium carbonate (20.36 gm, 147.6 mmol) and benzylbromide (15.14 gm, 88.56 mmol). The reaction was stirred at 50° C. for 6 hrs and then stirred at RT overnight. After this time, the reaction was poured into a 1:1 water: hexane mixture (2000 mL). The resultant mixture was stirred at r.t for 1 h. A solid precipitate formed and the precipitate was collected by filtration to give the title compound, 2-benzyl-6-(benzyloxy)-4,5-dichloropyridazin-3(2H)-one (23.9 gm, 90% yield) as light yellow solid. 1H(DMSO-D6) 7.45 (m, 2H), 7.35 (m, 4H), 7.30 (m, 4H), 5.26 (s, 2H), 5.17 (s, 2H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]2[N:16]([CH2:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]3)[CH:17]=[N:18][C:14]=2[CH:13]=[C:12]([Cl:27])[N:11]=1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:17]1[N:16]([CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]2)[C:15]2[C:10]([Cl:9])=[N:11][C:12]([Cl:27])=[CH:13][C:14]=2[N:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(Cl)c32)CC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(Cl)nc(Cl)c32)CC1
Temperature: 25 °C

Procedure:
N-bromosuccinimide (3.28 g, 18.4 mmol) was added to a solution of 4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (Preparative Example 2.3, 5 g, 16.8 mmol) stirring in degassed chloroform (168 mL) at room temperature. The reaction was heated to reflux for 1 hour. The mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated aqueous sodium thiosulfate (2×) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 2-bromo-4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine. MS ESI calc'd. for C14H16BrCl2N3 [M+H]+ 378. found 378.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([NH2:35])[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:28]=1.[CH3:36][C:37]1[CH:38]=[CH:39][C:40]([S:43]([OH:46])(=[O:45])=[O:44])=[CH:41][CH:42]=1>O1CCOCC1>[CH3:22][C:23]1[CH:24]=[C:25]([NH:35][C:2]2[N:7]=[C:6]([O:8][CH:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[CH:5]=[CH:4][N:3]=2)[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:28]=1.[S:43]([C:40]1[CH:41]=[CH:42][C:37]([CH3:36])=[CH:38][CH:39]=1)([O-:46])(=[O:45])=[O:44]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Reactant: Cc1cc(N)cc(-c2ccccc2)c1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(OC3CCNCC3)n2)cc(-c2ccccc2)c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate (62.8 mg, 0.2 mmol) and 5-methylbiphenyl-3-amine (36.6 mg, 0.2 mmol) in 0.1 M 1:1 TsOH:dioxane (2.0 mL) was heated to 100° C. overnight. Upon cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting light yellow solid was triturated in 1:1 dichloromethane:diethyl ether (10 mL). The solid was removed by filtration then dried under vacuum to provide N-(5-methylbiphenyl-3-yl)-4-(piperidin-4-yloxy)pyrimidin-2-amine as a tosylate salt as a light yellow solid. MS ESI calc'd. for C22H25N4O [M+H]+ 361, found 362. 1H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H); 8.68 (s, 2H); 8.29 (d, J=6.4 Hz, 1H); 7.76 (s, 1H); 7.63 (d, J=7.9 Hz, 1H); 7.61-7.26 (m, 1H); 7.21 (s, 1H); 7.12 (d, J=8.1 Hz, 2H); 6.43 (d, J=6.4 Hz, 1H); 5.26 (s, 1H); 3.19 (s, 2H); 2.97 (s, 2H); 2.29 (s, 2H); 2.14 (s, 2H); 1.95 (s, 3H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=[O:19])C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[CH2:35]2.CCOC(C)=O>CN(C)C=O>[O:49]=[C:43]1[CH:42]([N:36]2[C:35](=[O:19])[C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:10]([C:7]4[CH:6]=[CH:5][C:4]([S:3][CH2:1][CH3:2])=[CH:9][N:8]=4)=[O:12])[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCSc1ccc(C(=O)O)nc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
A stirred mixture of 5-ethylsulfanyl-pyridine-2-carboxylic acid (0.48 g, 2.60 mmol) and CDI (0.44 g, 2.70 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (1.0 g, 2.60 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×75 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (hexanes/EtOAc, gradient, product eluted at ˜85% EtOAc). The product fractions were combined and concentrated to give 5-ethylsulfanyl-pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.65 g, 60% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 7.53 min (97.70%); mp: 198-200° C.; 1H NMR (DMSO-d6) δ 1.28 (t, J=7.4 Hz, 3H), 2.00-2.16 (m, 1H), 2.53-2.67 (m, 2H), 2.79-3.02 (m, 1H), 3.13 (q, J=7.2 Hz, 2H), 4.65 (d, J=6.4 Hz, 2H), 5.14 (dd, J=5.4, 12.9 Hz, 1H), 7.72-8.06 (m, 5H), 8.54 (d, J=1.5 Hz, 1H), 9.53 (t, J=6.3 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 13.84, 21.99, 25.27, 30.93, 42.36, 48.99, 122.08, 122.18, 123.51, 129.78, 131.56, 133.56, 135.42, 137.99, 146.30, 146.37, 147.54, 164.07, 166.99, 167.13, 169.80, 172.72; LCMS: MH=453; Anal Calcd for C22H20N4O5S: C, 58.40; H, 4.46; N, 12.38. Found: C, 58.27; H, 4.35; N, 12.30.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)=[N:6][C:7]=1[Br:8].[CH3:14][N:15](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:9][CH2:10][C:11]([NH:15][CH3:14])=[O:13])=[N:6][C:7]=1[Br:8]
Reactant: Nc1ncc(CCC(=O)O)nc1Br
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CCc1cnc(N)c(Br)n1
Reaction time: 3 h
Yield: 74 %

Procedure:
To a solution of 3-(5-amino-6-bromopyrazin-2-yl)propanoic acid (32 mg, 0.130 mmol) in DMF (1300 μL) was added TBTU (62.6 mg, 0.195 mmol), DIEA (68.1 μL, 0.390 mmol), and methanamine hydrochloride (9.66 mg, 0.143 mmol). The reaction mixture was stirred for 3 h. The reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude 3-(5-amino-6-bromopyrazin-2-yl)-N-methylpropanamide (74%) was obtained and was used for the next step without further purification. LCMS (m/z): 259/261 (MH+), 0.35 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:12]([OH:15])(=[O:14])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:20](=[O:23])([O-])O.[Na+].[CH3:25][N:26](C)C=O>>[OH:23][CH2:20][CH2:25][NH:26][S:12]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:14])=[O:15]
Reactant: CN(C)C=O
Reactant: O=C([O-])O
Reactant: O=S(=O)(O)c1ccc(Cl)c2ncccc12
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: O=S(=O)(NCCO)c1ccc(Cl)c2ncccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To 14.2 g of 8-chloro-5-quinolinesulfonic acid were added 142 ml of thionyl chloride and 1.42 ml of dimethylformamide. The resultant mixture was heated under reflux for 3 hours and the thionyl chloride was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was dissolved in 100 ml of ice water and adjusted to pH 6 with a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with 100 ml of dichloromethane. The dichloromethane layer was added dropwise to 100 ml of a dichloromethane solution containing 3.56 g of ethanolamine and 5.6 g of triethylamine over 30 minutes while cooling with ice. The mixture was stirred at a temperature of 15° C. to 20° C. for 2 hours. After completion of the reaction, the resultant mixture was washed with 200 ml of water and dried over anhydrous magnesium sulfate. Then, the solvent was removed by distillation under reduced pressure, to thereby obtain 14.0 g of N-(2-hydroxyethyl)-8-chloro-5-quinolinesulfonamide (yield: 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH:18]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35](O)=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22]>>[CH3:17][CH:18]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(C)C(C)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CCCC(C)C(C)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
0.45 g of compound 22 was obtained in a similar manner to those described in the Examples 1 and 2 using 0.75 g of ethyl 4-(2-aminophenoxy)butyrate and 0.50 g of 3-[1-(1,2-dimethylpentyl)indol-5-yl]isocrotonic acid obtained according the procedures described in the Reference Examples 1-4.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4]C[CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:54])CC2)CC1>>[OH:54][CH:5]1[CH2:4][CH2:2][N:1]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: Cc1ccc(Oc2cccc3[nH]c(C(=O)NC4CCN(CCN5CCCCCC5)CC4)cc23)cc1
Agent: Cl
Product: Cc1ccc(Oc2cccc3[nH]c(C(=O)NC4CCN(CCN5CCC(O)CC5)CC4)cc23)cc1

Procedure:
This compound is synthesized analogously to Example 1 from 4-p-tolyloxy-1H-indole-2-carboxylic acid 137 (see example 115) and amine 21.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][CH:9]([O:17][CH:18]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1)[CH2:19][CH2:20]CO)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1.[CH:30]([Cl:33])(Cl)Cl>O>[Cl:3][CH2:6][CH2:7][CH2:8][CH:9]([O:17][CH:18]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1)[CH2:19][CH2:20][CH2:30][Cl:33])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1
Reactant: ClC(Cl)Cl
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C(CCCO)OC(CCCO)c2cccc(C)n2)n1
Solvent: O
Product: Cc1cccc(C(CCCCl)OC(CCCCl)c2cccc(C)n2)n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of sulphinyl chloride (260 g) in chloroform (450 cc) maintained at a temperature below 10° C., 3-hydroxypropyl(6-methyl-2-pyridyl)methyl ether (339 g) is added in the course of 30 minutes. The mixture is then heated gradually and then maintained boiling for 1 hour. After being cooled to about 20° C., the mixture is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The product obtained is dissolved in distilled water (1,000 cc) and the solution obtained is washed 3 times with diethyl ether (1,035 cc in total), filtered and then neutralised in the presence of diethyl ether (670 cc) with sodium bicarbonate (160 g). The decanted aqueous phase is saturated with sodium chloride and then extracted 3 times with diethyl ether (600 cc in total). The extracts are combined, dried over anhydrous magnesium sulphate in the presence of decolorising charcoal (17 g) and filtered. The filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa). 3-Chloropropyl(6-methyl-2-pyridyl)methyl ether (359.4 g) is thereby obtained in the from of a brown oil, and this is used as it is in the subsequent syntheses.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[NH4+].[NH4+]>C(#N)C.O.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[NH2:11])=[CH:6][N:7]=1
Reactant: Cc1ccc(N(CCc2ccc(Cl)nc2)N=O)cc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(N(N)CCc2ccc(Cl)nc2)cc1
Reaction time: 1 h

Procedure:
A 250 mL flask was charged with N-(2-(6-chloropyridin-3-yl)ethyl)-N-p-tolylnitrous amide (5.2 g, 18.9 mmol; Example 117C) and ammonium carbonate (3.62 g, 37.7 mmol; Aldrich) in acetonitrile (10 mL) and water (30 mL). The mixture was cooled in an ice bath and zinc dust (1.63 g, 24.5 mmol; Aldrich) was added very slowly over 2 hours. After stirring for an additional 1 hour, the reaction was filtered to remove the solid material. The filtrate was concentrated and extracted with ethyl acetate. The organic extracts were then purified by flash chromatography (silica gel, hexane/ethyl acetate, 2:1) to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.22 (s, 3H), 2.89-2.99 (m, 2H), 3.52-3.60 (m, 2H), 6.81-6.90 (m, 2H), 6.98-7.04 (m, 2H), 7.36 (d, J=8 Hz, 1H), 7.74 (dd, J=8, 3 Hz, 1H), 8.25 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 262 (M+H)+.
Reaction SMILES: [C:1]1(=[O:12])[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].CCCCCCCCCCCCCC[N:27](CCC)CCC>CO>[O:12]=[C:1]([NH2:27])[C@@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:9][OH:10])[OH:11])[OH:7])[OH:5])[OH:3]
Reactant: CCCCCCCCCCCCCCN(CCC)CCC
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CO
Product: NC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 40 °C
Reaction time: 8 h
Yield: 215.2 %

Procedure:
A 1 liter round bottom flask equipped with a condenser, addition funnel, thermometer and mechanical stirrer was charged with D-glucono-1,5-lactone (20.0 g, 0.11 mole) and methanol (56 g). The suspension was heated to 40° C. over 15 minutes and the heating mantle removed. Hydrogenated tallowaminopropylamine (36.0 g, 0.11 mole) was added dropwise over 15 minutes with rapid stirring. The reaction mixture was cooled and placed in a refrigerator at 0° C. overnight. The white product was filtered, washed with cold isopropanol (3×100 ml) and dried under vacuum at 35° C. giving 46.2 g (83% yield) of hydrogenated tallowaminopropyl D-gluconamide with a melting point of 112°-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:27][CH2:9][C:6]1[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)nc1-c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)nc1-c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 3-methoxy-6-methyl-2-(4-(trifluoromethyl)phenyl)pyridine (0.59 g, 2.2 mmol) in CCl4 (40 mL) was added NBS (440 mg, 2.5 mmol) and AIBN (33 mg, 0.20 mmol). The reaction mixture was heated to reflux for 13 h, diluted with EtOAc, washed with water (1×), brine (1×), dried over MgSO4, filtered through a pad (1.5 cm) of silica, and concentrated. The product 6-(bromomethyl)-3-methoxy-2-(4-(trifluoromethyl)phenyl)pyridine was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[C:21](=O)[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14]2)([F:12])[CH:6]2[C:10]=1[O:9][CH:8]([CH3:11])[CH2:7]2.P(Cl)(Cl)([Cl:25])=O.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[Cl:25][C:21]1[N:13]([C:5]2([F:12])[CH:6]3[CH2:7][CH:8]([CH3:11])[O:9][C:10]3=[C:2]([Cl:1])[CH:3]=[CH:4]2)[N:14]=[C:15]2[C:20]=1[CH2:19][CH2:18][CH2:17][CH2:16]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1CC2C(=C(Cl)C=CC2(F)n2[nH]c3c(c2=O)CCCC3)O1
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CC1CC2C(=C(Cl)C=CC2(F)n2nc3c(c2Cl)CCCC3)O1

Procedure:
0.25 g of 39C was mixed with 0.14 g of phosphorous oxychloride and 0.15 g of N,N-diethylaniline and heated under nitrogen at 135°-140° C. for three hours, cooled, and diluted with ethyl acetate. The organic phase was washed with water, 10% hydrochloric acid, saturated sodium bicarbonate solution, brine, dried (MgSO4) and stripped of solvent. The residue was purified by flash chromatography on silica gel, using a 1:4 v:v mixture of ether and hexane as eluent to afford the title compound as a yellow glass.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[C:15]([I:21])[N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].[CH2:22]([NH2:24])[CH3:23].CO>C(Cl)Cl>[I:21][C:15]1[N:16]=[C:17]([NH2:20])[C:18]2[N:19]=[C:2]([NH:24][CH2:22][CH3:23])[N:3]([C:13]=2[N:14]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: CCN
Reactant: Nc1nc(I)nc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: ClCCl
Solvent: CO
Product: CCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
The reaction was performed with 2-iodo-8-bromoadenosine (5, 90 mg, 0.19 mmol) and ethylamine (2.5 ml, 70% w/v in water). Yield 58.3 mg (0.13 mmol, 70%), mp 205–207÷C, Rƒ 0.15 (10% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 6.97 (t, 1H, J=5.15 Hz, NH), 6.89 (s, 2H, NH2), 5.79 (d, 1H, J=7.56 Hz, H-1′), 5.65–5.61 (m, 1H, OH-2′), 5.30 (d, 1H, J=6.18 Hz, OH-5′), 5.18 (d, 1H, J=3.77 Hz, OH-3′), 4.55 (q, 1H, J=6.17 Hz, H-2′), 4.08–4.04 (m, 1H, H-3′), 3.94 (bs, 1H, H-4′), 3.65–3.61 (m, 2H, H-5′), 2.49 (m, 2H, CH2), 1.16 (t, 3H, J=7.21 Hz, CH3); MS m/z 437 (M+H)+; Anal. (C12H17IN6O4) C, H, N.