Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:43])([CH3:42])[C@H:3]([NH:14][C:15]([C@H:17]([CH2:26]/[CH:27]=[CH:28]/[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:31]([CH3:41])[CH:30]=1)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:4]([O:6]CC1C=CC=CC=1)=[O:5]>C(O)C.O.[Pd]>[CH3:1][C:2]([CH3:43])([CH3:42])[C@H:3]([NH:14][C:15]([C@H:17]([CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:31]([CH3:41])[CH:30]=1)[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:16])[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(/C=C/C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc2ccccc2)C(C)(C)C)ccc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Cc1cc(CCC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)O)C(C)(C)C)ccc1-c1ccccc1
Yield: 97 %

Procedure:
A solution of tert-butyl (3R,5E)-3-({[(1S)-2,2-dimethyl-1-(benzyloxycarbonyl)propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hex-5-enoate (2.205 g, 3.78 mmol) in ethanol/water=10:1 (44 mL) was hydrogenated over 10% palladium on charcoal at 3 bar and room temperature for 6 h. The mixture was filtered through Arbocel filter aid, washing well with ethanol. The filtrate was concentrated under reduced pressure. The residue was dissolved in toluene and evaporated (three times), dissolved in ether and evaporated (twice), and finally dissolved in ether and precipitated as an oil by the addition of hexane. Removal of the solvent under reduced pressure gave tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-(carboxy)propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hexanoate (1.817 g, 97%) as a colourless foam, m.p. 51-56° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[S:14](Cl)(=[O:16])=[O:15])([O-:3])=[O:2].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([S:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:16])=[O:15])[CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-nitro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (1.0 g, 1.73 mmol) in CH2Cl2 (50 mL) was added 1-methylpiperazine (0.40 mL, 3.6 mmol). The resulting mixture was allowed to stir at room temperature overnight, then diluted with CH2Cl2 (30 mL), the organic layer was washed with 9% aq. Na2CO3 (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH2:23][CH:24]([OH:26])[CH3:25]>>[OH:26][CH:24]([CH3:25])[CH2:23][NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: CC(O)CN
Product: CC(O)CNc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 65 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 1-amino-propan-2-ol according to the GPA affording 23.1 mg (65%) of a red powder. Rt=3.07 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]#[N:10].[BH4-].[Na+].O>CC(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]#[N:10]
Reactant: N#C/C=C/c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: N#CCCc1ccccn1
Temperature: 80 °C
Reaction time: 14 h
Yield: 83.6 %

Procedure:
(E)-3-(2-Pyridyl)acrylonitrile (0.50 g, 3.8 mmol) was dissolved in 2-propanol (10 ml), and sodium borohydride (0.50 g, 13.2 mmol) was added thereto. The reaction mixture was stirred at 80° C. for 14 hrs and cooled under ice cooling condition, combined with water, concentrated to the half amount and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (25 g) column chromatography. The fractions eluted with hexane-ethyl acetate (1:1, v/v) were collected and concentrated to give the titled compound (0.42 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:21])[C@H:16]([CH:18]([CH3:20])[CH3:19])[NH2:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:31]([C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](O)=[O:37])#[N:32].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH:14][C:15](=[O:21])[C@H:16]([CH:18]([CH3:20])[CH3:19])[NH:17][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][CH:41]=[C:33]([C:31]#[N:32])[CH:34]=3)[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](N)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cccc(C#N)c1)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-{(valylamino)methyl}piperidine (20 mg, 0.059 mmol) in CH2Cl2 (0.60 mL) was treated with Et3N (0.011 mL, 0.077 mmol), m-cyanobenzoic acid (28 mg, 0.071 mmol), EDCI (13 mg, 0.065 mmol) and HOBt (9 mg, 0.065 mmol). The reaction mixture was stirred at 25° C. for 16 h. The resulting solution was diluted with CH2Cl2 (0.75 mL), washed with 2 N aqueous NaOH solution (2×0.75 mL) and dried by filtration through a PTFE membrane. Concentration afforded the 1-(4-chlorobenzyl)-4-[{N-(3-cyanobenzoyl)valyl}aminomethyl]piperidine (compound No. 619) (24.2 mg, 88%) which required no further purification: The purity was determined by RPLC/MS (85%); ESI/MS m/e 467 (M++H, C26H31ClN4O2).
Reaction SMILES: Cl.Cl.Cl[CH2:4][C:5]1[N:6]=[C:7]([CH2:10][N:11]([CH3:13])[CH3:12])[S:8][CH:9]=1.[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([OH:35])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH:18]=[CH:19][C:20]=1[Cl:21].C(=O)([O-])[O-].[K+].[K+]>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:4][C:5]4[N:6]=[C:7]([CH2:10][N:11]([CH3:13])[CH3:12])[S:8][CH:9]=4)=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CN(C)Cc1nc(CCl)cs1
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1csc(CN(C)C)n1
Temperature: 25 °C
Reaction time: 50 h
Yield: 15 %

Procedure:
N-{[4-(Chloromethyl)-1,3-thiazol-2-yl]methyl}-N,N-dimethylamine hydrochloride hydrochloride (0.050 g, 0.220 mmol) and 4-[(3,4-dichlorophenyl)amino]-6-(methoxy)quinazolin-7-ol (0.074 g, 0.220 mmol) were suspended in DMP (4 mL) and potassium carbonate (0.152 g, 1.10 mmol) was added. The mixture was stirred at room temperature for 50 h and then at 70° C. for 3.5 h. An additional portion of N-{[4-(chloromethyl)-1,3-thiazol-2-yl]methyl}-N,N-dimethylamine hydrochloride hydrochloride (0.019 g, 0.084 mmol) was added and the mixture was stirred at 70° C. for a further 25 h. The reaction mixture was concentrated in vacuo. and the residue was partitioned between ethyl acetate and brine. The organic portion was washed with 1 N aqueous sodium hydroxide, brine, dried over sodium sulfate, filtered and concentrated in vacuo. to afford a brown solid. Recrystallization from ethyl acetate/diethyl ether afforded the title compound as a pale brown solid (0.016 g, 0.033 mmol, 15% yield). 1H NMR (400 MHz; CDCl3): 2.37 (s, 6H); 3.79 (s, 2H); 4.00 (s, 3H); 5.34 (s, 2H); 7.00 (s, 1H); 7.15 (br s, 1H); 7.34-7.37 (m, 2H); 7.55 (d, 1H); 7.57 (d, 1H); 7.96 (d, 1H); 8.66 (s, 1H); MS (EI) for C22H21Cl2N5O2S: 490 (MH+).
Reaction SMILES: [OH:1][CH:2]([CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[S:7]([CH3:10])(=[O:9])=[O:8].[OH-].[Na+].O>C(O)C>[OH:1][CH:2]([CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:7]([CH3:10])(=[O:9])=[O:8]
Reactant: CCOC(=O)CCCCCCN(CCCC(O)COc1ccc(F)cc1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)N(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Reaction time: 20 h

Procedure:
A solution composed of ethyl 7-{N-[4-hydroxy-5-(4-fluorophenoxy)pentyl]methanesulfonamido}heptanoate (4.7 g., 0.11 mole), sodium hydroxide (1.0 g.), water (13 ml.) and ethanol (130 ml.) is kept at room temperature for 20 hours. Most of the solvent is removed in vacuo, water (150 ml.) is added and the solution extracted with ether (100 ml.). The aqueous layer is acidified (hydrochloric acid) and extracted with ethyl acetate (2 × 100 ml.). The organic layer is dried over sodium sulfate then concentrated in vacuo to obtain the subject compound. The yield is 3.7 g. (84%) of heavy oil.
Reaction SMILES: [Li]C(C)(C)C.[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH:22]=[O:23]>C1COCC1>[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][C:15]=1[CH:22]([C:18]1[S:17][CH:21]=[CH:20][N:19]=1)[OH:23]
Reactant: COCOc1cccc(C)c1
Reactant: O=Cc1nccs1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCOc1cc(C)ccc1C(O)c1nccs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of t-BuLi (1.7 M in pentane, 5.0 mL, 8.5 mmol), 1-(methoxymethoxy)-3-methylbenzene (see example 33, step 1) was added dropwise (1.18 g, 7.73 mmol), maintaining the internal temperature below 16° C. The suspension was stirred at 0° C. for 1 h, cooled to −78° C., and THF (15 mL) was added. A solution of 1,3-thiazole-2-carboxaldehyde (0.962 g, 8.5 mmol) was added and the cooling bath was removed. The reaction mixture was allowed to warm to 0° C., extracted twice with EtOAc from NH4Cl, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (30-50% EtOAc in hexanes) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 7.77 (d, 1H), 7.48 (s, 1H), 7.33 (d, 1H), 6.95 (s, 1H), 6.83 (d, 1H), 6.36 (d, 1H), 5.32 (d, 1H), 5.21 (s, 2H), 3.38 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]([C@@H:11]2[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:12]2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]=1[CH2:8][C:9]#[N:10])#[N:2].[NH3:41]>CO>[NH2:2][C:1]1[C:3]2[N:4]=[CH:5][N:6]([C@@H:11]3[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@@H:21]([O:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@@H:12]3[O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:7]=2[CH:8]=[C:9]([NH2:41])[N:10]=1
Reactant: N
Reactant: N#CCc1c(C#N)ncn1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: CO
Product: Nc1cc2c(ncn2[C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)c(N)n1

Procedure:
A mixture of 6.0 g of 4-cyano-5-cyanomethyl-1-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)imidazole and 300 ml of dry methanol saturated at 0° C. with ammonia is kept in a steel bomb at ambient temperatures for 24 hours and then evaporated in vacuo to dryness. The residue is triturated with ether, dissolved in methanol, absorbed on silica gel, and chromatographed over silica gel with chloroform-methanol (10:1) to provide 4.0 g of 4,6-diamino-1-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)imidazo[4,5-c]pyridine.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH:31]([NH:34][CH3:35])([CH3:33])[CH3:32]>>[CH:31]([N:34]([CH3:35])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)([CH3:33])[CH3:32]
Reactant: CNC(C)C
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: CC(C)N(C)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and isopropyl(methyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.96 (m, 3H), 7.59 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 3.3-3.8 (m, 13H), 2.88 (s, 3H), 1.40 (d, 6.3 Hz, 3H), 1.36 (d, 6.3 Hz, 3H); MS (DCI) m/z 408 (M+H)+;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[S:19]1[C:23]([S:24](Cl)(=[O:26])=[O:25])=[CH:22][C:21]2[CH:28]=[CH:29][CH:30]=[CH:31][C:20]1=2>C(Cl)Cl.N1C=CC=CC=1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([S:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][S:24]([C:23]2[S:19][C:20]3[CH:31]=[CH:30][CH:29]=[CH:28][C:21]=3[CH:22]=2)(=[O:25])=[O:26])(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a solution of N-(2-aminophenyl)-4-chlorobenzenesulfonamide (0.5 mmol, prepared as in Example 11) in DCM (1 mL) and pyridine (1 mL), benzo[b]thiophene-2-sulfonyl chloride (0.55 mmol), prepared as above, was added at RT and the reaction mixture was then allowed to stir at RT overnight or until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to afford 180 mg of benzo[b]thiophene-2-sulfonic acid [2-(4-chlorobenzenesulfonylamino)phenyl]-amide. LC: Tr 1.23 min, MS: 479.8 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4](OS(C)(=O)=O)[CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[I-:21].[Na+]>CC(=O)CC>[CH3:1][O:2][C:3](=[O:20])[CH:4]([I:21])[CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: COC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COC(=O)C(I)CCO[Si](C)(C)C(C)(C)C
Temperature: 90 °C

Procedure:
A solution of 2.89 g (8.85 mmol) of (S)-4-(tert-butyl-dimethyl-silanyloxy)-2-methanesulfonyloxy-butyric acid methyl ester in 90 ml of 2-butanone was treated with 2.65 g (17.70 mmol) of sodium iodide and stirred at 90° C. for 1¼ h. The reaction was cooled, filtered and evaporated. The residue was suspended in dichloromethane treated with Na2SO4 and filtered to give after evaporation 2.94 g (93%) of the title compound as dark brown oil. MS: 343.0 (M-CH3)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[O:22])[N:9]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Reactant: COCCN
Product: COCCNC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) are dissolved in 30 ml of 2-methoxyethylamine and the mixture is stirred at room temperature for 2 h. It is concentrated to dryness in vacuo and the residue is crystallized from isopropanol. After drying, 2-[3,5-Bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-methoxyethyl)acetamide remains as colorless crystals of m.p. 184-186° C.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:39]=[CH:40][CH:41]=1)[CH2:17][N:18]([CH2:29][C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1.CCN(CC)CC>O=S(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[CH2:29][N:18]([CH2:17][C:16]1[CH:15]=[C:14]([CH:41]=[CH:40][CH:39]=1)[CH2:13][NH:12][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[N:10][C:2]=1[CH3:1])[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: Cc1ccnc(C)c1C(=O)O
Reactant: NCc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1ccnc(C)c1C(=O)NCc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A solution of 2,4-dimethyl-nicotinic acid (56 mg, 0.37 mmol) in SOCl2 (˜3 mL, excess) was heated to 80° C. for 4 hours. The condenser was removed and the mixture was flushed with N2 at 80° C. for ˜5 minutes and then dried in vacuo for 10 minutes. The resulting syrup was dissolved in CH2Cl2 (2.0 mL) and added to a stirring mixture of (3-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (147 mg, 0.37 mmol), Et3N (0.26 mL, 1.85 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred ovemight at room temperature. Purification of the crude yellow foam by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:1:1) followed by radial chromatography on silica gel (1 mm plate, EtOAc/MeOH/NH4OH, 200:1:1) afforded the desired amide (85 mg, 43%) as a light yellow foam.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:9][C@@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]1[CH:29]=[C:17]2[N:18]=[C:19]([NH2:28])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]2[N:15]=1>N1C=CC=CC=1>[CH3:13][C:14]1[CH:29]=[C:17]2[N:18]=[C:19]([NH:28][C:10]([C@H:8]3[CH2:9][C@@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]2[N:15]=1
Reactant: O=C(Cl)[C@H]1C[C@@H]1c1ccccc1
Reactant: Cc1cc2nc(N)cc(-c3ccccc3)n2n1
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)[C@H]3C[C@@H]3c3ccccc3)cc(-c3ccccc3)n2n1
Temperature: 25 °C

Procedure:
In a round-bottomed flask was (1S,2S)-2-phenylcyclopropanecarbonyl chloride (161 mg, 0.892 mmol) added in Pyridine (3 mL) to give a yellow suspension. 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine (10A, 100 mg, 0.446 mmol) was added portionwise at 0° C. The temperature was slowly raised to room temperature. The reaction was quenched with saturated sodium bicarbonate and partitioned between ethyl acetate and water. The separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure (3×100 mL). The reaction mixture was filtered and purified by preparatory HPLC (70-80% MeCN/H2O gradient+0.01% TFA). Received 46 mg (28%) of yellow solid. 1H NMR (DMSO-d6) δ: 11.28 (s, 1H), 7.94-8.06 (m, 2H), 7.90 (s, 1H), 7.52-7.68 (m, 3H), 7.27-7.35 (m, 2H), 7.16-7.26 (m, 3H), 6.33 (s, 1H), 2.42-2.49 (m, 1H), 2.28-2.43 (m, 4H), 1.50-1.57 (m, 1H), 1.44 (ddd, J=8.1, 6.5, 4.0 Hz, 1H); [α]D20=+294° (c=0.6060, MeOH). ESI-MS: m/z 369.0 (M+H)+.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:4]2[CH:5]=[CH:6][C:1]([CH3:12])=[CH:2][CH:3]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Cc1ccc(C2CCCN2)cc1
Product: Cc1ccc(C2CCCN2S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound, white solid, m.p. 129° C. and MS: m/e=335 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-p-tolyl-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:13]=3[N:14]=2)=[CH:5][CH:4]=1)[CH3:2].[H][H]>[Pd].CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:13]=3[N:14]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCc1ccc(Nc2nc3cc([N+](=O)[O-])ccc3o2)cc1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(Nc2nc3cc(N)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
20 mL of methanol was slowly added dropwise to the compound (b) prepared in Preparation 2 (1.31 mmol, 1 eq) and 5% Pd/C (0.4 g), and then the reaction mixture was charged with hydrogen and stirred at room temperature for 24 hours.
Reaction SMILES: [CH3:1][N:2]([CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[S:3]([C:6]1[CH:25]=[CH:24][C:9]2[N:10]([CH3:23])[C:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)=[N:12][C:8]=2[CH:7]=1)(=[O:5])=[O:4].[ClH:33].C(=O)([O-])[O-].[NH4+:38].[NH4+]>>[ClH:33].[CH3:1][N:2]([CH:26]1[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]1)[S:3]([C:6]1[CH:25]=[CH:24][C:9]2[N:10]([CH3:23])[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21](=[NH:38])[NH2:22])=[CH:19][CH:20]=3)=[N:12][C:8]=2[CH:7]=1)(=[O:4])=[O:5]
Reactant: [NH4+]
Reactant: CN1CCC(N(C)S(=O)(=O)c2ccc3c(c2)nc(COc2ccc(C#N)cc2)n3C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Product: CN1CCC(N(C)S(=O)(=O)c2ccc3c(c2)nc(COc2ccc(C(=N)N)cc2)n3C)CC1

Procedure:
Prepared analogously to Example 25d from 400 mg of 1-methyl-2-[(4-cyanophenyl)oxymethyl]benzimidazol-5-yl-sulfonic acid-N-methyl-N-(1-methylpiperidin-4-yl)amide with ethanolic hydrochloric acid and ammonium carbonate.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[OH:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(B(O)O)c1O
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4cccc(C)c4O)n3)n2)c1
Yield: 65 %

Procedure:
6-(2-Hydroxy-5-methoxyphenyl)-6′-(2-hydroxy-3-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-3-methylphenylboronic acid in 65% yield using method F; δH [2H6]-DMSO 12.35,(1H, s), 8.37,(2H, m), 8.24,(2H, m), 8.17,(1H, d), 7.96,(1H, d), 7.65,(1H, s), 7.27,(1H, d), 7.02-6.86,(3H, m), 3.83,(3H, s), 8.09,(1H, s); MS 385 (MH)+; HPLC retention time (system 1) 4.31 minutes.