Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[Na:16].C(=O)([O-])[O-].[Na+].[Na+]>O>[S:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][CH:10]=1)([OH:4])(=[O:3])=[O:2].[Na:16]
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CCC(=O)Nc1ccc(S(=O)(=O)O)cc1
Reaction time: 96 h

Procedure:
Solid sodium N-(4-sulfophenyl)acrylamide (250 mg; 1 mmol) and solid sodium carbonate (106 mg; 1 mmol) were added successively to a stirred solution of PAMAM 4.0 (EDA) (78 mg; 0.011 mmol) in water (4 ml). The resulting solution was stirred under nitrogen for four days and then freeze dried to give a fluffy white solid. The crude product was purified by gel filtration (Sephadex LH20; water to give PAMAM 4.0 (EDA) terminated with 64 sodium N-(4-sulfophenyl)propanamide groups (206 mg). 13C nmr showed a faint trace of what was taken to be mono alkylated terminal amino groups. 1H nmr (D2O):δ 2.10; 2.48; 2.58; 2.79; 3.20; 7.42 (d, J=7 Hz); 7.65 (d, J=7 Hz). 13C nmr (D2O): δ 36.5; 37.9; 41.1; 53.4; 55.6; 124.8; 130.9; 143.0; 144.2; 177.4; 178.5.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7]CC)=O)[CH2:3][CH2:2]1.[C:12]1([CH3:19])[C:13](Br)=[CH:14][CH:15]=[CH:16][CH:17]=1.[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1>>[C:12]1([CH3:19])[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[N:1]1[CH2:2][CH2:3][CH:4]([C:5]([N:20]2[CH2:25][CH2:24][S:23][CH2:22][CH2:21]2)=[O:7])[CH2:10][CH2:11]1
Reactant: C1CSCCN1
Reactant: Cc1ccccc1Br
Reactant: CCOC(=O)C1CCNCC1
Product: Cc1ccccc1N1CCC(C(=O)N2CCSCC2)CC1

Procedure:
The title compound was prepared from commercially available ethyl isonipecotate, o-tolyl bromide as the aryl halide, and thiomorpholine as the secondary amine utilizing general procedures A and B described above. 1H NMR (300 MHz, CDCl3) δ 7.19-7.13 (m, 2H), 7.00-6.95 (m, 2H), 3.95 (m, 2H), 3.82 (m, 2H), 3.21 (m, 1H), 3.17 (m, 1H), 2.71-2.54 (m, 7H), 2.30 (s, 3H), 2.09 (dd, J=3.6, 13.1 Hz, 1H), 2.00 (dd, J=3.6, 12.0 Hz, 1H), 1.79 (m, 1H), 1.75 (m, 1H). ESI MS: 305.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.S(Cl)([Cl:12])=O.N#N.[O-]S([O-])(=O)=O.[Ca+2]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][Cl:12]
Reactant: OCc1ccncc1Cl
Reactant: O=S(Cl)Cl
Agent: N#N
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Product: Cl
Product: ClCc1ccncc1Cl
Temperature: 25 °C

Procedure:
Solid 3-chloro-4-hydoxymethylpyridine (33.8 g, 0.235 mol) was added cautiously over 8 min to stirred thionyl chloride (72 ml, 0.706 mol) cooled in an ice bath and under a stream of N2. After addition the yellow solution was heated in an oil bath at 50° and protected under a tube of Drierite. After 30 min the solution was removed from the oil bath, allowed to cool to ambient temperature, and poured into a flask of stirred anhydrous ether (1,000 ml).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:18])[CH2:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-].[Na]>CO.C(OCC)(=O)C.ClCCl>[CH3:10][O:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH2:1][OH:9])=[CH:4][CH:5]=1)=[O:16]
Reactant: COC(=O)CCC(=O)Cl
Reactant: OCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(CCO)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
To a dry 250 mL flask under a nitrogen atmosphere was added phenethyl alcohol (2.50 g, 0.02 mol), anhydrous dichloromethane (150 mL), and methyl-4-chloro-4-oxobutyrate (6.02 g, 0.04 mol). The contents of the flask were cooled to 0° C. with an ice bath. To the solution was added aluminum chloride (25 g, 0.2 mol) in portions being careful to avoid a violent exotherm. The resulting yellowish mixture was stirred for 3 hours. At this point the reaction was quenched with ice water. The mixture was diluted with dichloromethane and transferred to a separatory funnel. The organic layer was washed with a saturated solution of sodium bicarbonate, brine and then dried over magnesium sulfate. Filtration and concentration of the filtrate under reduced pressure provided a crude yellow oil. The oil was suspended in anhydrous methanol (100 mL) and sodium metal was added to the mixture until a pH of 9 was obtained. The mixture was stirred for 3 hours. The volume was reduced and then diluted with ethyl acetate. The solution was transferred to a separatory funnel and washed with aqueous 0.05 N hydrochloric acid, brine and dried over magnesium sulfate. The solution was concentrated under reduced pressure to give a crude yellow oil with a mass of 5.88 g. Column chromatography [silica gel; eluent hexanes-ethyl acetate (3:2)] provided the desired product (2.69 g, 57%). 1H(CDCl3) δ(ppm): 2.65 (t, 2H); 2.81 (t, 2H); 3.19 (t, 2H); 3.6 (s, 3H); 3.75 (t, 2H); 7.22 (d, 2H); 7.81 (d, 2H). 13C(CDCl3) δ(ppm): 27.76, 33.03, 38.66, 51.52, 62.68, 127.97, 128.99, 134.47, 144.78, 173.21, 197.64.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Br[CH2:13][CH3:14].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:13][CH3:14])=[O:10])=[CH:6][CH:7]=1
Reactant: CCBr
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(Cl)cc1
Reaction time: 18 h
Yield: 623.3 %

Procedure:
A solution of 25 grams (0.147 mole) of 4-chlorophenylacetic acid in 250 ml of acetonitrile was stirred and 15.0 grams (0.0147 mole) of bromoethane, followed by 22.0 grams (0.147 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene, were added. Upon completion of addition the reaction mixture was cooled in a water bath while being stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to one-half volume and then was added to 50 ml of water. The mixture was extracted with two portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 18.2 grams of ethyl (4-chlorophenyl)acetate.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH3:10])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[OH2:17].[C:18](#[N:20])[CH3:19]>>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:20][C:18](=[O:17])[CH3:19])[CH3:10])=[CH:5][CH:4]=1
Reactant: O
Reactant: CC#N
Reactant: CC(O)c1ccc(CCl)cc1
Agent: O=S(=O)(O)O
Product: CC(=O)NC(C)c1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a solution of 1-(4-chloromethylphenyl)ethanol (17 g) in acetonitrile (102 ml) was added dropwise conc. sulfuric acid (5.7 ml) under ice-cooling. The mixture was stirred at 0° C. for 3.5 hr and left standing overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a white solid. This solid was recrystallized from ethyl acetate-isopropyl ether to give the title compound (17 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([OH:22])=O)[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:22])[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1COCCN1
Reactant: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Product: C[C@H]1C(=O)N(CCC(=O)N2CCOCC2)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 45 %

Procedure:
In analogy to the procedure described in Example 15, 3-[(S)-4-(3,4-dichloro-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-propionic acid (intermediate 12) and morpholine gave the titled compound in 45% yield as white foam. MS: 441.1 (M−H−, 2Cl).
Reaction SMILES: N[C@H](C(N1C(=O)N[C@H]2[C@@H]1CS[C@H]2C[CH2:13][CH2:14][CH2:15][C:16](=[O:18])O)=O)CS.[CH3:23][C:24](N(O)CCCCCNC(CCC(N(O)CCCCCNC(CCC(N(O)CCCCCN)=O)=O)=O)=O)=[O:25].CS(O)(=O)=O.[OH-].[Na+].C1C(=O)N([O:76][C:77]([CH2:79]I)=[O:78])C(=O)C1.CC(N(O)CCCCCNC(CCC(N(O)CCCCCNC(CCC(N(O)CCCCCN)=O)=O)=O)=O)=O>CO>[CH3:23][C:24]([O:13][CH2:14][CH:15]([O:78][C:77]([CH3:79])=[O:76])[CH:16]=[CH2:18])=[O:25]
Reactant: CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN
Reactant: O=C(CI)ON1C(=O)CCC1=O
Reactant: N[C@@H](CS)C(=O)N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CC(COC(C)=O)OC(C)=O

Procedure:
DACB was synthesized by covalently conjugating iodoacetyl-deferoxamine and N-cysteinyl-biotin by the following Scheme II. ##STR20## Solid deferoxamine mesylate was added to methanol for a concentration of 20 mM, followed by addition of NaOH to reach a final concentration of 20 mM NaOH. The solution was heated and maintained at 65°. Solid iodoacetic acid N-hydroxysuccinimide ester (NHS-IA) was added to the deferoxamine solution to a final molarity of 50mM NHS-IA and incubated for at least one hour at 65°. The resulting iodoacetyl-deferoxamine (IA-DFO) was purified by HPLC with an EM LiChroCART reverse phase column using a linear gradient of 0-10 ml 100% Buffer A (0.025M phosphate, pH 6, 2 mM NTA) and 10-60 ml 0-100% Buffer B (0.025M phosphate, pH 6, 2 mM NTA, 75% methanol). IA-DFO, but not unconjugated DFO, has an absorbance at 260 nm and thus was purified by measuring the absorbance of the eluate and collecting the fraction with absorbance at 260 nm.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1.ClC1[CH:35]=[C:34]([O:36]C2C=CC([N+]([O-])=O)=CC=2)[N:33]=CN=1.C(N)(=O)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:26][C:25]([F:28])([F:27])[C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:33][C:34](=[O:36])[CH3:35])[CH:3]=3)=[CH:10][CH:11]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Nc1ccc(Oc2cc(Cl)ncn2)cc1)Nc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Agent: [Pd]
Agent: CC(N)=O
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ncn1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
1-[4-(6-Chloro-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea (compound of Example 56) (100 mg, 0.245 mmol)1 acetamide (40 mg1 0.678 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthrene (9 mg), and tris(dibenzylideneacetone)dipalladium (6 mg) dissolved in dioxane (3 mL) are stirred at 55° C. under Ar for 8 h. After evaporating the solvent under reduced pressure, the residue is partitioned between H2O (60 mL) and AcOEt (200 mL). The organic phase is separated, dried (MgSO4) and concentrated under reduced pressure. The product is purified by preparative thin layer chromatography (four 20×20 cm silica gel plates, acetone/CH2Cl2=3:7): M+H=431.9; Rf (acetone/CH2Cl2=3:7): 0.29; 1H-NMR (400 MHz, DMSO-d6): 10.85 (s, 1H, pyrimidinyl), 9.03/8.84 (s/s, 1H/1H, urea), 8.45 (s, 1H, NH), 7.98 (s, 1H, pyrimidinyl), 7.56 (d, 8.5 Hz, 1H, phenyl-CF3), 7.50 (d/s, 9.0 Hz, 2H/1H, phenyl/phenyl-CF3), 7.49 (t, 1H, phenyl-CF3), 7.29 (d, 8.5 Hz, 1H, phenyl-CF3), 7.06 (d, 9.0 Hz, 2H, phenyl), 7.39 (d, 8.5 Hz, 2H), 7.13 (s, 1H), 7.11 (d, 8.5 Hz, 2H), 6.86 (d, 8.5 Hz, 2H), 5.94 (s, 1H, pyrimidinyl), 2.09 (s, 3H, CH3).
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C([Li])CCC.CCCCCC.[Cl:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH:26]=[CH:27][CH:28]=[O:29].C(=O)(O)[O-].[Na+]>CCOCC.O1CCCC1>[Br:8][C:6]1[CH:7]=[C:2]([CH:28](/[CH:27]=[CH:26]/[C:25]2[CH:30]=[CH:31][C:32]([Cl:33])=[C:23]([Cl:22])[CH:24]=2)[OH:29])[C:3]([O:9][CH3:10])=[N:4][CH:5]=1
Reactant: O=CC=Cc1ccc(Cl)c(Cl)c1
Reactant: COc1ncc(Br)cc1Br
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ncc(Br)cc1C(O)/C=C/c1ccc(Cl)c(Cl)c1
Temperature: -78 °C

Procedure:
A solution of 60.6 g of 3,5-dibromo-2-methoxypyridine in 900 ml of anhydrous ether was stirred under nitrogen and cooled to -78° C. to give a thick slurry. Efficient stirring was used to prevent the solid starting material from adhering to the wall of the reaction vessel. While the temperature was maintained below -65° C., 85 ml of 2.67M n-butyllithium/hexane was added dropwise. The reaction mixture was homogeneous upon completion of the addition and it was stirred for 15 minutes at -78° C. Then, a solution of 45.6 g of 3,4-dichlorocinnamaldehyde in 200 ml of anhydrous tetrahydrofuran was added dropwise while keeping the temperature below -65° C. When the addition was complete, 100 ml of aqueous saturated sodium bicarbonate solution was added to the cold reaction mixture. It was then allowed to warm to about -40° C. and then partitioned between ether and aqueous saturated sodium bicarbonate solution. The aqueous layer was extracted with ether and the combined ether layers were washed with aqueous saturated sodium chloride solution, dried over potassium carbionate, filtered and concentrated to leave a pale yellow solid. This was recrystallized from a mixture of 2-propanol/ethyl acetate/hexane (1:3:5) to give (E)-5-bromo-α-[2-(3,4-dichlorophenyl)ethenyl]-2-methoxy-3-pyridinemethanol melting at about 149°-150° C.
Reaction SMILES: [CH2:1]([CH:8]1[C:14](=[O:15])[C:13](=[N:16]O)[CH:12]2[CH2:18][CH:9]1[CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:19].[H][H]>[Pd].C(O)C>[ClH:19].[NH2:16][CH:13]1[CH:12]2[CH2:18][CH:9]([CH2:10][CH2:11]2)[CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:14]1=[O:15]
Reactant: O=C1C(=NO)C2CCC(C2)C1Cc1ccccn1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NC1C(=O)C(Cc2ccccn2)C2CCC1C2
Reaction time: 3 h
Yield: 86 %

Procedure:
A solution of 2-aza-2-benzyl-4-oximino-3-oxobicyclo[3.2.1]octane in 10 mL/mmole of ethanol and 5.8 mL/mmole of 3N HCl containing 0.5 g/mmole of 10% Pd/C was saturated with hydrogen gas to 45 psi. The mixture was shaken for 3 hours and then filtered through a layer of Celite. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as a solid (86% yield). This procedure is further described in E. Reimann, Arch. Pharm. 310, 102-109 (1977).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].[CH:38](=O)[CH2:39][CH2:40][CH3:41]>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Reactant: CCCC=O
Product: CCCCN[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) as described in general procedure F using butyraldehyde. The final product was obtained in 13% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:20]=3[N:19]=[CH:18]2)=[CH:13][CH:12]=1.[C:29](N1C=CN=C1)([N:31]1C=CN=C1)=O.Cl.CN.CCN(C(C)C)C(C)C>C1COCC1>[CH3:29][NH:31][C:26]([C:24]1[CH:23]=[CH:22][C:21]2[N:17]([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:16][CH:15]=3)[CH:18]=[N:19][C:20]=2[CH:25]=1)=[O:27]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc2c(c1)ncn2-c1ccc(OCCOc2ccccn2)cc1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)ncn2-c1ccc(OCCOc2ccccn2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1-{4-[2-(Pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxylic acid (100 mg, 0.266 mmol) and 1,1′-carbonyldiimidazole (86 mg, 0.53 mmol) were dissolved in dry THF (2 mL) under a N2 atmosphere. The reaction mixture was heated at 60° C. for 1 h and then cooled to rt. Methylamine hydrochloride (27 mg, 0.40 mmol) and N,N′-diisopropylethylamine (52 mg, 0.40 mmol, 70 μL) were added and the reaction was allowed to stir at rt. After 18 h, the reaction mixture was concentrated in vacuo, diluted with CH2Cl2 (2 mL), and washed with distilled water (1 mL). The aqueous phase was back extracted with CH2Cl2 (2 mL×5) and the combined organic extracts were concentrated in vacuo. The resulting yellow solid was purified using the Waters mass-directed HPLC purification system to give N-methyl-1-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxamide as a white powder. 1H NMR (d6-DMSO, 400 MHz): δ 8.57 (s, 1H), 8.49 (brq, J=4.4 Hz, 1H), 8.28 (d, J=1.2 Hz, 1H), 8.19 (ddd, J=5.2, 2.0, 0.8 Hz, 1H), 7.85 (dd, J=8.6, 1.4 Hz, 1H), 7.74 (ddd, J=8.8, 6.8, 2.0 Hz, 1H), 7.61 (ddd, J=5.2, 3.2, 3.2 Hz, 2H), 7.55 (d, J=9.2 Hz, 1H), 7.23 (ddd, J=5.8, 3.6, 3.6 Hz, 2H), 7.01 (ddd, J=7.2, 5.2, 1.2 Hz, 1H), 6.88 (ddd, J=8.4, 0.8, 0.8 Hz, 1H), 4.63 (m, 2H), 4.43 (m, 2H), 2.82 (d, J=4.8 Hz, 3H). MS(ES+): m/z 389 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31]>>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][CH2:23][N:15]1[C:14]2[C:19]([N:20]=[C:12]([S:11][C:4]3[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:13]=2)=[C:18]([NH2:21])[N:17]=[CH:16]1
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Reactant: Clc1ccccc1CCBr
Product: COc1ccc(OC)c(Sc2nc3c(N)ncn(CCc4ccccc4Cl)c-3n2)c1

Procedure:
The title compounds were prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-(2-bromo-ethyl)-2-chloro-benzene by a procedure similar to examples 1 and 2. The isomers were separated by preparative HPLC. 9-[2-(2-Chloro-phenyl)-ethyl]-8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine: Yield 18%, 1H NMR (DMSO-d6) δ 8.23 (s, 1H), 7.82 (bs, 2H), 7.36 (dd, J=8.0, 1.2 Hz, 1H), 7.24-7.15 (m, 2H), 7.03-6.99 (m, 2H), 6.85 (dd, J=9.2, 3.2 Hz, 1H), 6.47 (d, J=2.8 Hz, 1H), 4.46 (t, J=7.2 Hz, 2H), 3.73 (s, 3H), 3.61 (s, 3H), 3.16 (t, J=7.2 Hz, 2H); LC-MS [M+H]+ 442.1. 3-[2-(2-Chloro-phenyl)-ethyl]-8-(2,5-dimethoxy-phenylsulfanyl)-3H-purin-6-ylamine: Yield, 11%, 1H NMR (DMSO-d6) δ 8.34 (s, 1H), 8.16 (bs, 1H), 7.41 (m, 1H), 7.29-7.11 (m, 6H), 4.56 (t, J=6.8 Hz, 2H), 3.76 (s, 3H), 3.72 (s, 3H), 3.30 (t, J=6.8 Hz, 2H), LC-MS [M+H]+ 442.1.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][CH2:19][C:20](NC1SC=CN=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][N:36]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.Cl>[CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][CH2:19][C:20]([NH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][N:36]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: O=C(CCC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1nccs1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1ccc(C(=O)O)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Example 1, Part E (300 mg, 1.02 mmol) was taken up in 4 mL CH2Cl2 and cooled to 0° C. Oxalyl chloride (0.1 mL, 1.22 mmol) was added slowly and stirring continued for 0.5 h. A slurry of 6-aminonicotinic acid (211 mg, 1.53 mmol) and diisopropylethylamine (0.27 mL, 1.53 mmol) was added slowly and stirring continued at room temperature for 16 h. Three drops of conc. HCl was added and the organic phase was washed with brine. The organic phase was dried (Na2SO4), filtered and evaporated. The product was purified by silica gel chromatography (12 mg, 3%). 1H NMR (400 MHz, CDCl3) δ 10.69 (s, 1H), 8.70 (m, 1H), 8.32 (m, 1H), 7.87 (m, 1H), 7.52 (m, 3H), 7.34 (m, 6H), 5.46 (m, 1H), 4.60 (br s, 1H), 4.31 (m, 1H), 2.54 (m, 2H), 2.09 (m, 2H). MS: m/z (MH+) 416.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26].Cl>C(#N)C>[CH2:25]([N:15]1[CH2:16][CH2:17][N:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:9])=[O:10])[C:2]=2[F:1])[CH2:13][CH2:14]1)[CH3:26]
Reactant: CS(=O)(=O)c1cccc(N2CCNCC2)c1F
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCN(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 1-[2-fluoro-3-(methylsulfonyl)phenyl]piperazine (0.13 g, 0.52 mmol), acetonitrile (4 ml), potassium carbonate (0.14 g, 1.1 mmol) and iodoethane (0.48 ml, 0.52 mmol). Yield: 0.09 g (60%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 214-216° C. MS m/z (relative intensity, 70 eV) 286 (M+, 59), 272 (14), 271 (87), 201 (11), 57 (bp).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH2:27][NH:26][CH2:25][CH2:24]4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.O.NN>CN(C=O)C.O>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH2:27][N:26]([S:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:39])=[O:38])[CH2:25][CH2:24]4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1ccc2c(c1)CCNC2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: NN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1ccc2c(c1)CCN(S(=O)(=O)c1ccccc1)C2
Yield: 64.8 %

Procedure:
25 mg (0.049 mmol) of 1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide, 0.01 mL of (0.07 mmol) benzenesulfonyl chloride, and 0.07 mL of (0.5 mmol) triethylamine in 0.5 mL DMF was stirred at room temperature for 1 h. The reaction mixture was then treated with 0.024 mL of hydrazine hydrate and diluted with water. The precipitated solid was filtered and washed with water to give 2-benzenesulfonyl-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide (17.2 mg, 65%). LCMS: 542 (M+1)+.