Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([N:27]2[CH2:28][CH2:29][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH3:17])[CH2:25][CH2:26]2)=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(C(=O)c2c(C)noc2-c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (0.100 g, 0.35 mmol), 1-(2-methylphenyl)piperazine (0.092 g, 0.52 mmol), and 1-hydroxybenzotriazole (0.096 g, 0.71 mmol) in 5:1 CH2Cl2:DMF was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.136 g, 0.71 mmol), and the reaction was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 and washed twice with H2O, once with brine, and then dried over Na2SO4, filtered, and concentrated to give the title compound, which was used directly in the following step.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.[Na+].CN(C)CCN.O>CS(C)=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1Br
Reactant: O=S([O-])c1ccc(Br)cc1
Agent: CN(C)CCN
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccccc1S(=O)(=O)c1ccc(Br)cc1
Temperature: 110 °C
Yield: 54.9 %

Procedure:
2-Bromobenzaldehyde (1.55 g, 8.4 mmol), sodium 4-bromophenylsulfinate (2.79 g, 10 mmol) and copper(I) trifluoromethanesulfonate benzene complex (500 mg, 1 mmol) were combined in dimethylsulfoxide (10 mL) under nitrogen and degassed. The suspension was heated to 110° C. and N,N-dimethylethylenediamine (176 mg, 2 mmol) was added. The reaction was heated until the colour became clear and pale yellow, then cooled and poured into water. The products were extracted into ethyl acetate. The organic layer was washed with water:brine (1:1, ×5), dried over MgSO4 and evaporated in vacuo. The residue was triturated with isohexane to give 2-[(4-bromophenyl)sulfonyl]benzaldehyde (1.5 g, 55%). δH (400 MHz, CDCl3): 10.76 (1H, s), 8.14-8.12 (1H, m), 7.98-7.96 (1H, m), 7.76-7.68 (4H, m), 7.64-7.62 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][N:34]([CH:36]([CH3:39])[C:37]#[N:38])[CH:35]=2)O1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:31]3[CH:32]=[N:33][N:34]([CH:36]([CH3:39])[C:37]#[N:38])[CH:35]=3)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Reactant: CC(C#N)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4cnn(C(C)C#N)c4)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (Example 34, Step 1). LCMS (M+H)+=444.0/446.0. 1H NMR (300 MHz, DMSO-d6) δ: 9.72 (s, 1H), 8.72 (s, 1H), 8.33 (s, 1H), 7.04 (s, 1H), 5.92 (q, J=7.1 Hz, 1H), 3.97 (s, 6H), 1.88 (d, J=7.1 Hz, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][N:17]=[N:16][N:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(Cl)(=O)C.Cl>CO>[NH:18]1[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][N:16]=[N:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CO
Product: C1CC(c2nnn[nH]2)CCN1
Reaction time: 2.5 h

Procedure:
To 100 mg of the solid from Step A was added a solution of 0.30 mL of acetyl chloride in 5 mL of methanol (generates a methanol solution of hydrochloric acid). After 2.5 hours at room temperature, the reaction was evaporated to dryness, triturated twice with ether and vacuum dried to give the title compound as a tan solid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:23]2[CH:30]=[CH:29][S:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:20][C:17]1[CH:18]=[CH:19][N:6]2[C:7]=1[C:8](=[O:16])[N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([C@@H:2]([NH:1][C:22]1[C:23]3[CH:30]=[CH:29][S:28][C:24]=3[N:25]=[CH:26][N:27]=1)[CH3:3])=[N:5]2
Reactant: Clc1ncnc2sccc12
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4sccc34)n(-c3ccccc3)c(=O)c12
Yield: 57.5 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.16 mmol) was treated with 4-chlorothieno[2,3-d]pyrimidine (31 mg, 0.18 mmol) and N,N-diisopropylethylamine (171 μl, 0.98 mmol) in 1-butanol according to the method described in Example 17. The crude was purified using SP1® Purification (0% to 60%, hexane-ethyl acetate) to give 37 mg (56% yield) of the title compound as a solid. Purity 99%.
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][C@@H:55]([N:57]2[CH2:62][CH2:61][C@H:60]([OH:63])[C@@H:59]([CH3:64])[CH2:58]2)[CH3:56])CC1>>[ClH:43].[ClH:1].[OH:63][C@H:60]1[CH2:61][CH2:62][N:57]([C@@H:55]([CH3:56])[CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:58][C@@H:59]1[CH3:64]
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)c3cc4c(OCc5coc6ccc(Cl)cc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized from 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97, see example 42) and amine 56 analogously to the method described in example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[CH:12][N:11]=2.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[CH:12][N:11]=2)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1-c1nc2cccnc2o1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1-c1nc2cccnc2o1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
An ice cold solution of 1 gram of 2-(2-aminophenyl)oxazolo[ 5,4-b]pyridine in 15 ml. of dry pyridine was treated with 1 gram of benzoyl chloride slowly. The reaction mixture was diluted with ice-water and stirred for 10 minutes and the resulting solid was collected on a filter and recrystallized from benzene to give 2-(2-benzoylaminophenyl)oxazolo[ 5,4-b]pyridine, m.p. 197°-198° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
5% Palladium on carbon (“wet”, 11.1 g) was added to a solution of N-(4-nitro-phenyl)-methanesulfonamide (Example 3a′, 111.4 g, 0.52 mol) in tetrahydrofuran (900 mL) at 25° C. The atmosphere above the resulting suspension was replaced with hydrogen gas and the reaction mixture was maintained under 1 atmosphere of hydrogen at 25° C. for 4 days using several balloons. The mixture was then filtered through Celite and the Celite was washed with tetrahydrofuran (3×100 mL). The combined filtrate and washings were concentrated in vacuo to approximately 300 mL volume and heptane (500 mL) was added dropwise via addition funnel over 45 min at 25° C. with vigorous stirring. The resulting suspension was stirred for an additional 45 min at 25° C., and then was filtered through medium paper using a Büchner funnel. The collected solid was washed with heptane (1×150 mL) and was air-dried to afford the desired product, N-(4-amino-phenyl)-methanesulfonamide (90.7 g, 0.49 mol, 95% yield) as a beige powder. 1H NMR (400 MHz, DMSO-d6) δ 2.79 (3H, s), 5.00 (2H, s), 6.49 (2H, d, J=8.5 Hz), 6.87 (2H, d, J=8.6 Hz), 8.87 (1H, s).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[N:25]=[C:24]([O:26][CH2:27][CH2:28][N:29]5[C:37](=[O:38])[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[C:30]5=[O:39])[CH:23]=[CH:22][N:21]4[C:40]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.[OH-].[Na+]>CO.C(Cl)Cl.O1CCOCC1>[NH2:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[N:25]=[C:24]([O:26][CH2:27][CH2:28][N:29]5[C:37](=[O:38])[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[C:30]5=[O:39])[CH:23]=[CH:22][N:21]4[C:40]=3[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(OCCN5C(=O)c6ccccc6C5=O)ccn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4nc(OCCN5C(=O)c6ccccc6C5=O)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
[1-(4-{7-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-3-phenyl-imidazo[1,2-a]pyrimidin-2-yl}-phenyl)-cyclobutyl]-carbamic acid tert-butyl ester (530 mg) was dissolved in methanol/DCM (1.3 mL/2.1 mL), treated with HCl in dioxane (4.08 mL of a 4M solution) and the mixture stirred overnight at rt. The reaction mixture was poured onto ice, made alkaline with 2N aqueous sodium hydroxide and extracted with EtOAc. The combined organic phases were washed with saturated aqueous sodium chloride, dried and concentrated in vacuo to give the crude title product as a yellow oil. Purification was achieved by trituration at 0° C. with diisopropyl ether. The resulting precipitate was filtered and dried to give the title compound as a solid (390 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[N:7][N:6]2[CH:12]=1.[OH-].[NH4+:14]>>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([CH:12]=[C:3]([CH2:2][NH2:14])[N:4]=2)[N:7]=1
Reactant: [NH4+]
Reactant: Cc1ccc2nc(CCl)cn2n1
Agent: [OH-]
Product: Cc1ccc2nc(CN)cn2n1
Temperature: 80 °C

Procedure:
A mixture of 2-(chloromethyl)-6-methylimidazo[1,2-b]pyridazine (0.6 g, 3.3 mmol) and ammonium hydroxide (25%, 30 ml) was heated to 80° C. in a sealed tube for lhr. The reaction mixture was concentrated under reduced pressure to give title compound as crude product. This material was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CC(C)=O.O>[CH2:13]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:10])([F:11])[F:12])=[CH:3][C:2]=1[Br:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)c1ccc(OCc2ccccc2)c(Br)c1
Yield: 84.6 %

Procedure:
A solution of 3-bromo-4-hydroxybenzotrifluoride (6.03 g, 25 mmol) in acetone (1000 ml) was treated with benzyl bromide (4.67 g, 3.25 ml, 27.5 mmol) and potassium carbonate (5.18 g, 37.5 mmol). The mixture was stirred and heated to reflux under nitrogen for 2 h. After cooling, diethyl ether (300 ml) and water (300 ml) were added and the aqueous phase re-extracted with diethyl ether (100 ml). The combined organic layers were washed with water, dried (MgSO4) and the solvent removed in vacuo. The orange oil was flash chromatographed (silica gel, 2-5% dichloromethane-isohexane) to give the title compound as a clear oil (7.0 g, 85%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][O:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][N:12]=1>>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: BrCCOc1cc(-c2ccccc2)on1
Product: c1ccc(-c2cc(OCCN3CCOCC3)no2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
Morpholine (871 mg) was added to 3-(2-bromoethoxy)-5-phenylisoxazole (268 mg), and the mixture was stirred at 100° C. for one hour. After ice-cold water (20 ml) was added to the reaction mixture and the resulting mixture was extracted with ether (20 ml×2), the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the title compound (250 mg, 91%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH2:16][C:15]([C:21]4[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]([Cl:29])[CH:22]=4)([C:17]([F:20])([F:19])[F:18])[O:14][N:13]=3)=[CH:8][CH:7]=2)[CH2:5][NH:4][CH2:3]1.N1C=CC=CC=1.[C:36](Cl)(=[O:38])[CH3:37].O>C(Cl)Cl>[F:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH2:16][C:15]([C:21]4[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]([Cl:29])[CH:22]=4)([C:17]([F:19])([F:20])[F:18])[O:14][N:13]=3)=[CH:8][CH:7]=2)[CH2:3][N:4]([C:36](=[O:38])[CH3:37])[CH2:5]1
Reactant: FC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)CNC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparation 9, 94 mg) in 2 mL CH2Cl2 was added pyridine (0.05 mL) followed by acetyl chloride (31 mg). The reaction was allowed to stir at room temperature for 1 hour. Water (3 mL) was added. The reaction was diluted with 3 mL of CH2Cl2, stirred for 30 minutes and poured through a phase extractor. The CH2Cl2 layer was collected and concentrated. The crude product from the reaction was adsorbed onto silica and chromatographed on a 12 g silica column eluting with a gradient of 50% EtOAc/hexanes to 100% EtOAc/hexanes to yield 90 mg of the desired compound as a white foam. 1H NMR (CDCl3) δ 7.76 (d, 2H). 7.67 (s, 2H), 7.56 (d, 2H), 4.71-4.31 (m, 4H), 4.12 (d, 1H), 3.72 (d, 1H), 2.01 (s, 3H). LC/MS retention time=3.591 minutes; MS calculated for (C21H15Cl3F4N2O2), 509.714; found 511 M+H.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:37]3[N:36]=[C:30]([NH:31][C:32](=[S:35])[NH:33][CH3:34])[NH:29][C:27](=[O:28])[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:47]1([N:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:54](Cl)=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])[O:12][C@@H:11]([N:23]2[C:37]3[N:36]=[C:30]([NH:31][C:32](=[S:35])[NH:33][CH3:34])[N:29]=[C:27]([O:28][C:54](=[O:55])[N:53]([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CNC(=S)Nc1nc2c(ncn2[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: O
Product: CNC(=S)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
The above-obtained 3′,5′-bis-O-(tert-butyldimethylsilyl)-2-N-methylthiocarbamoyldeoxyguanosine (1.0 g, 1.76 mmol) was azeotroped with anhydrous pyridine three times and dissolved in anhydrous pyridine (17 mL). To the resulting solution, diisopropylethylamine (511 μL, 3.16 mmol) and then diphenylcarbamoyl chloride (489 mg, 2.11 mmol) were added. The mixture was stirred at room temperature for 0.5 hours, and then sodium bicarbonate water (5 mL) was added thereto to terminate the reaction. Then, the reaction solution was extracted with ethyl acetate (150 mL)/sodium bicarbonate water (120 mL) once and then with ethyl acetate (150 mL)/brine (100 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (N60: spherical neutral silica gel) with ethyl acetate/40% to 50% hexane to give 3′,5′-bis-O-(tert-butyldimethylsilyl)-6-O-diphenylcarbamoyl-2-N-methylthiocarbamoyldeoxyguanosine (1.09 g, 81%).
Reaction SMILES: [NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([N:19]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][N:18]=[C:13]2[CH:12]([CH3:42])[CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC(C1C=C(C(C)C)C(S([N:68]=[N+:69]=[N-:70])(=O)=O)=C(C(C)C)C=1)C.CC(O)=O>C1COCC1.CCOC(C)=O>[NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([N:19]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][N:18]=[C:13]2[C@@:12]([N:68]=[N+:69]=[N-:70])([CH3:42])[CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@]1(N=[N+]=[N-])C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 71.3 %

Procedure:
To a solution of the methyl diastereomers (12c) (1.02 g, 1.78 mmol) in 10 mL THF at −78° C., was added LiHMDS (1M in THF, 3.73 mL, 3.73 mmol). The red solution was stirred at −78° C. for 10 min, then a solution of trisyl azide (606 mg, 1.96 mmol) in 2 mL THF was added. The reaction was stirred at −78° C. for 1.5 h, then was quenched with the addition of AcOH (459 μL, 8.01 mmol). The mixture was stirred at rt for 1 h, then was diluted with EtOAc. The organic phase was washed with sat. NH4Cl and brine, dried (Na2SO4), and concentrated. The product was purified by flash chromatography (30 to 35% EtOAc/hexanes) to afford 784 mg (71%) of azide (12d). 1H NMR (300 MHz, CDCl3) δ9.26 (br s, 1H), 7.82 (br s, 1H), 7.51-7.25 (m, 13H), 7.10 (t, J=7.3, 1H), 5.23 (m, 3H), 4.91-4.77 (m, 2H), 2.90 (d, J=13.9, 1H), 2.43 (dd, J=13.6, 9.2, 1H), 1.87 (s, 3H); MS (ESI) 640.4 (M+Na+), 616.4 (M−H+).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]1[S:8][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:11]=1.[NH2:16][C:17]1[O:21][N:20]=[C:19]([CH3:22])[C:18]=1[Br:23]>>[Br:23][C:18]1[C:19]([CH3:22])=[N:20][O:21][C:17]=1[NH:16][S:12]([C:9]1[S:8][C:7]([C:6]2[CH:5]=[CH:4][O:3][C:2]=2[CH3:1])=[CH:11][CH:10]=1)(=[O:14])=[O:13]
Reactant: Cc1occc1-c1ccc(S(=O)(=O)Cl)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccoc3C)s2)c1Br
Yield: 53.1 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyl-furanyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-(2-methylfuranyl)thiophene-5-sulfonyl chloride (55 mg, 0.21 mmol) with 5-amino-4-bromo-3-methyl isoxazole (41 mg, 0.21 mmol), after purification by column chromatography using 10% MeOH/CHCl3, gave 45 mg of the pure sulfonamide as a brown semisolid, 54% yield, m.p. 123°-124° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2C2OC3=CC=CC3=CC=2)=[O:11])=[CH:4][CH:3]=1.[C:38]1(=[O:44])[O:43][C:41](=[O:42])[CH2:40][CH2:39]1.O1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>C(OCC)C.C1(C)C=CC=CC=1>[O:48]1[C:49]2=[CH:50][CH:4]=[CH:3][C:2]2=[CH:7][CH:46]=[C:47]1[N:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:10]([CH:9]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:41](=[O:42])[CH2:40][CH2:39][C:38]([OH:43])=[O:44])=[CH:7][CH:6]=1)=[O:11]
Reactant: C1COCCO1
Reactant: CC(C)(C)c1ccc(C(Cc2ccc(N)cc2)C(=O)Nc2ccccc2-c2ccc3cccc-3o2)cc1
Reactant: O=C1CCC(=O)O1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(Cc2ccc(NC(=O)CCC(=O)O)cc2)C(=O)N(c2ccccc2)c2ccc3cccc-3o2)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 5 %

Procedure:
To 3-(4-Amino-phenyl)-N-(4-benzofuran-2-yl-phenyl)-2-(4-tert-butyl-phenyl)-propionamide (100 mg, 0.2 mmol) in 2 ml diethyl ether, 2 ml toluene and 1 ml 1,4-dioxane was added succinic anhydride (22 mg, 0.22 mmol). The reaction mixture was stirred at 23° C. for 16 h, concentrated, and loaded to reverse phase silica gel. After chromatography (from 20% acetonitrile to 80% acetonitrile in water in 12 column volume), the fractions containing the desired product were collected and concentrated. The residue was diluted with methanol (1 ml) and water was added dropwise until the precipitate stop forming. The white precipitate was removed by filtration and dried under high vacuum at 50° C. to afford the title compound (6.3 mg, 5%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[O:24])[CH:17]=1)[C:10]([CH3:33])([CH3:32])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:32][C:10]1([CH3:33])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCN(C)CC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN1CCN(C(=O)Nc2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 15.7 %

Procedure:
A mixture of 3,3-dimethyl-2-{3-[(4-methyl-piperazine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (612 mg, 1.36 mmol) in methanol (15 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-{3-[(4-methyl-piperazine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (90 mg, 22%) as a white solid: LC/MS m/e calcd for C24H30N4O3 (M+H)+: 423.53, observed: 423.2.