Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][C:19]=1[CH3:29]>C1(C)C=CC=CC=1>[CH3:29][C:19]1[CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:27]=[CH:28][C:18]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(Br)c(C)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
Into 150 ml of water were suspended 55.9 g of sodium carbonate and 38.6 g of phenylboronic acid. Thereto was added 51.4 g of ethyl 4-bromo-3-methylbenzoate dissolved in 400 ml of toluene and then was added 4.0 g of tetrakistriphenylphosphine palladium, followed by 2 hours of reflux with heating. After the reaction solution was cooled to room temperature, filtration was conducted using celite, water was added to the filtrate and the organic layer was extracted with toluene. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by evaporation and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 50.4 g of ethyl 2-methylbiphenyl-4-carboxylate as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][N:12](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2c[nH]cn2)c1
Yield: 69.5 %

Procedure:
A solution of 4-(3-cyanophenyl)-1-trityl-1H-imidazole (0.07 g, 0.17 mmol) in tetrahydrofuran (1.36 mL) was treated with 2N hydrochloric acid (0.68 mL) and the resulting mixture was heated at reflux for 45 minutes. After cooling the reaction mixture was concentrated in vacuo and the residue dissolved in dichloromethane (20 mL). The organic phase was successively washed with 1N sodium hydroxide (10 mL), water (20 mL) and brine (20 mL). The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography of the residues using 3% methanol in dichloromethane afforded 0.02 g (72%) of 4-(3-cyanophenyl)imidazole as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC.[F-].[Cs+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:15]=[CH2:16])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1nc(C(=O)OC)c(Cl)c(N)c1F
Temperature: 90 °C
Yield: 67.3 %

Procedure:
A solution of methyl 4-amino-3,6-dichloro-5-fluoropyridine-2-carboxylate (8.00 g, 33.0 mmol), tributyl(vinyl)tin (13.27 g, 42.0 mmol) and cesium fluoride (11.19 g, 73.6 mmol) in dimethylformamide (250 mL) was sparged with nitrogen for 15 minutes. Dichlorobis(triphenylphosphine)palladium (II) (1.17 g, 1.6 mmol) was then added and the mixture was heated at 90° C. overnight. After cooling, the mixture was concentrated, taken up into ethyl acetate and filtered through a silica gel plug. The solvents were removed and the crude product was purified by column chromatography (50% ethyl acetate in hexane) to give methyl 4-amino-3-chloro-5-fluoro-6-vinylpyridine-2-carboxylate (5.13 g, 22.2 mmol), mp 68-71° C.
Reaction SMILES: C([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])[N:15]=[N:14][N:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)(C)(C)C.Cl.[OH-].[Na+]>CO>[F:24][C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[N:16]1[C:12]([C:11]2[C:6]([NH2:5])=[N:7][CH:8]=[CH:9][CH:10]=2)=[N:13][N:14]=[N:15]1
Reactant: CC(C)(C)Nc1ncccc1-c1nnnn1-c1cccc(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncccc1-c1nnnn1-c1cccc(F)c1F

Procedure:
Crude N-tert-butyl-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine was dissolved in MeOH (10 mL), treated with 6N HCl (20 mL), and heated to reflux for 2 hours. The mixture was subsequently cooled to RT and neutralized with 6N NaOH. The resulting precipitate was collected, washed with water, and dried in vacuo to give 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine as white solid. Using the same procedure, 3-(1-(2,3-dichlorophenyl)-H-tetrazol-5-yl)pyridin-2-amine and 3-(1-(3-chloro-2-fluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine can be produced from N-tert-butyl-3-(1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine and N-tert-butyl-3-(1-(3-chloro-2-fluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine, respectively.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:16][CH2:15]2)[N:5]=1>>[OH:22][CH:21]([C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=1)[CH2:20][N:17]1[CH2:18][CH2:19][N:14]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[CH:12]=[CH:13][C:4]([CH3:3])=[N:5]3)[CH2:15][CH2:16]1
Reactant: CC(=O)Nc1cccc(C(=O)CN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC(=O)Nc1cccc(C(O)CN2CCN(c3cccc4nc(C)ccc34)CC2)c1

Procedure:
Sodium borohydride (0.015 g, 1.6 eq) was added to a stirred solution of N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]acetyl}phenyl)acetamide
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([NH2:36])(=[O:35])=[O:34])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.IC1C=CC=CC=1S(N)(=O)=O>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33]([NH2:36])(=[O:35])=[O:34])=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccccc2S(N)(=O)=O)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: NS(=O)(=O)c1ccccc1I
Product: NS(=O)(=O)c1ccccc1-c1cnc(C(=O)CCCCCCc2ccccc2)o1
Yield: 44 %

Procedure:
2-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)benzenesulfonamide. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (71 mg, 0.107 mmol) and 2-iodobenzenesulfonamide following General Procedure A. Flash chromatography (2-10% EtOAc/hexanes) yielded the title compound as a clear oil (25 mg, 44%): 1H NMR (CDCl3, 400 MHz) δ 8.18 (d, 1H, J=7.6 Hz), 7.62-7.59 (m, 2H), 7.54-7.51 (m, 1H), 7.42-7.39 (m, 1H), 7.36 (s, 1H), 7.24-7.22 (m, 2H), 7.16-7.12 (m, 2H), 5.29 (ex s, 2H), 4.88 (t, 1H, J=6.7 Hz), 2.56 (t, 2H, J=7.6 Hz), 1.86-1.84 (m, 2H), 1.62-1.59 (m, 2H), 1.31-1.29 (m, 6H). 0.86 (s, 9H), 0.09 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 170.7, 153.6, 148.0, 144.9, 137.9, 135.7, 134.6, 134.3, 133.6, 133.4, 133.3, 131.0, 130.8, 42.3, 41.1, 36.3, 34.9, 34.3, 34.3, 31.0, 30.0, 23.5, 0.4, 0.0.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[N:11](S(C4C=CC(C)=CC=4)(=O)=O)[C:10]=3[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[K+].[Li+].[OH-].Cl>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1cc2c(n1S(=O)(=O)c1ccc(C)cc1)CCC2Cc1ccc(F)cc1
Agent: Cl
Agent: [K+]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
The title compound was synthesized from methyl 4-(4-fluorobenzyl)-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate in two steps. First, the starting material's methyl ester was hydrolyzed according to General Procedure 7. In this case, 0.070 g (0.274 mmol) of starting ester and potassium hydroxide (10 M, 0.16 mL, 1.6 mmol) were used. The deprotected methyl ester (4-(4-fluorobenzyl)-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid) (0.035 g, 0.13 mmol) was then dissolved in THF (3 mL) and MeOH (3 mL), and LiOH (0.055 g, 1.3 mmol) in H2O (3 mL) was added and the reaction stirred at 70° C. for 6 h. The reaction was diluted in 25 mL H2O and acidified to pH 2-3 with 1 N HCl, then extracted with 2×50 mL EtOAc. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound. 16 mg. 19F NMR δ ppm −102.42 (m, J=5.4) LCMS-MS (ESI−) 258.0 (M−H); HPLC (UV=98.52%), (ELSD=100%).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH3:9][CH:10]([O-:12])[CH3:11].[Na+]>CC(O)C>[CH:10]([O:12][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1)([CH3:11])[CH3:9]
Reactant: Cc1cnc(Br)cn1
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cnc(OC(C)C)cn1
Temperature: 115 °C
Yield: 37.9 %

Procedure:
To a solution of 2-bromo-5-methylpyrazine (3 g, 17.34 mmol) in 2-propanol (14 mL) was added sodium propan-2-olate (3.56 g, 43.3 mmol) and heated under microwave irradiation at 115° C. for 1.1 h. The organic solvent was evaporated before water was added to the residue. The mixture was extracted with dichloromethane (2×75 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a brown oil (1.0 g). LCMS m/z=153.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (d, J=6.19 Hz, 6H), 2.39 (s, 3H), 5.10-5.20 (m, 1H), 7.84 (s, 1H), 7.99 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:21]([C:23]1[CH:24]=[C:25]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[C:26]([O:28][CH3:29])=[O:27])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(O)(=O)C.CCOC(C)=O>[C:15]([O:14][C:13]([NH:12][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@H:3]([OH:20])[CH2:2][NH:1][CH2:21][C:23]1[CH:24]=[C:25]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[C:26]([O:28][CH3:29])=[O:27])=[O:19])([CH3:17])([CH3:16])[CH3:18]
Reactant: COC(=O)c1cc(C=O)cc(OC)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (300 mg, 1.07 mmol) in THF was added methyl 3-formyl-5-methoxybenzoate (294 mg, ˜80% purity, 1.07 mmol) and stirred for 30 min at room temperature, NaB(OAc)3H (453.7 mg, 2.14 mmol) was then added portionwise in 30 min, finally 5 drops of acetic acid was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was separated and dried (MgSO4). Concentration in vacuo, followed purification with flash chromatography to give the desired product methyl 3-(((2R,3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutylamino)methyl)-5-methoxybenzoate as a white solid (390 mg, % yield). 1H NMR (CDCl3): d: 8.583 (s, 1H), 7.447 (s, 1H), 7.298-7.166 (m, 5H), 7.092 (s, 1H), 3.899 (s, 3H), 3.832 (s, 4H), 3.779 (s, 2H), 3.572 (m, 1H), 2.2.946 (m, 1H), 2.777 (m, 1H), 2.711 (m, 2H), 1.330 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([Mg]Cl)(C)(C)C.[Mg].C(Cl)(C)(C)C.Cl>ClC1C=CC=CC=1.CCOCC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][O:13][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(C)(O)C(=O)O
Agent: CC(C)(C)[Mg]Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: Clc1ccccc1
Solvent: O
Product: CC(C)(OCc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Reaction time: 1 h
Yield: 15.8 %

Procedure:
A solution of 4-(4-chlorophenyl)benzaldehyde (41.5 g.) in chlorobenzene (250 ml.) containing in addition 2-hydroxy-2-methylpropionic acid (29.7 g.) and p-toluenesulphonic acid monohydrate (2.7 g.) was heated under reflux for 6 hours at reduced pressure (105° C., 313 mm Hg) with continuous removal of water by azeotropic distillation. The solution was then cooled, washed successively with 10% w/v sodium carbonate solution (500 ml.) and water (2×500 ml.), dried (MgSO4), filtered and diluted with fresh chlorobenzene to a volume of 350 ml. to give a solution containing 14.3% w/v of 2-[4-(4-chlorophenyl)-phenyl]-5,5-dimethyl-1,3-dioxolanone-4-one, as estimated by gas-liquid chromatography. This solution (35 ml.) was added during 1 hour at 0° to 5° C. under an argon atmosphere to a stirred solution of t-butyl magnesium chloride [prepared from magnesium turnings (1.61 g.) and a solution of t-butyl chloride (9.33 ml.) in anhydrous ether (40 ml.)]. The mixture was stirred for 1 hour at 0° to 5° C. and then for a further 16 hours at room temperature before being poured into 1.5 M hydrochloric acid (100 ml.). The organic phase was separated and washed with water (2×100 ml.), dried (Na2SO4) and evaporated to give 2-[4-(4-chlorophenyl)benzyloxy]-2-methyl-propionic acid (9.23 g.), m.p. 154°-155° C., after recrystallisation from toluene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:32])[F:33])=[C:26]([O:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:2]1[N:1]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: FC(F)Oc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: O=C(O)Cc1ncccn1
Product: O=C(Cc1ncccn1)N1CCN(c2ccc(OC(F)F)c(OC3CCC3)c2)C[C@@H]1Cc1ccccc1

Procedure:
Prepared by the method outlined for Example 189 using pyrimidin-2-yl-acetic acid and (S)-3-benzyl-1-(3-cyclobutoxy-4-difluoromethoxy-phenyl)-piperazine (Example 4, Compound 92) as starting materials. Product as an oil. LC/MS (Method B) 2.86 min, [M+1]+ 509. Potency class B.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[CH2:31][CH:32]=O)[NH:27][C:26](=[O:34])[CH2:25][CH2:24]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[CH2:31][CH2:32][N:1]1[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=4)[CH:9]=[CH:8]3)[CH2:5][CH2:6]1)[NH:27][C:26](=[O:34])[CH2:25][CH2:24]2
Reactant: NC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Reactant: COc1cc2c(cc1CC=O)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2c(cc1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
100 mg of 1-(piperidin-4-yl)-1H-indole-6-carboxamide and 87 mg of (6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)acetaldehyde were suspended in 5 ml of methylene chloride. Thereafter, 0.05 ml of acetic acid and 0.13 g of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was stirred at room temperature overnight. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) and by NH silica gel column chromatography (chloroform-methanol), and then reprecipitated from ethyl acetate, so as to obtain 18 mg of the subject compound.
Reaction SMILES: O([CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])S(C(F)(F)F)(=O)=O.[Cl:22][C:23]1[CH:24]=[C:25]([CH:57]=[CH:58][CH:59]=1)[NH:26][C:27]1[N:32]=[C:31]([C:33]2[N:34]=[CH:35][N:36](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:37]=2)[CH:30]=[CH:29][N:28]=1>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([CH:57]=[CH:58][CH:59]=1)[NH:26][C:27]1[N:32]=[C:31]([C:33]2[N:34]([CH2:9][CH2:10][N:11]3[C:15](=[O:16])[C:14]4=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]4[C:12]3=[O:21])[CH:35]=[N:36][CH:37]=2)[CH:30]=[CH:29][N:28]=1
Reactant: Clc1cccc(Nc2nccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)n2)c1
Reactant: O=C1c2ccccc2C(=O)N1CCOS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCn1cncc1-c1ccnc(Nc2cccc(Cl)c2)n1
Reaction time: 0.08 h
Yield: 40 %

Procedure:
2-Phthalimidoethyl triflate (660 mg, 2.04 mmol) was added to solution of the 2-(3-chloroanilino)-4-(1-triphenylmethylimidazol-4-yl)pyrimidine Method 2; 1.00 g, 1.95 mmol) in DCM (5 ml) and the reaction mixture stirred for 4 hours. The solvent was removed by evaporation and MeOH (6 ml) and 2M hydrochloric acid (1.5 ml) was added to the residue. The mixture was stirred for 5 minutes, the volatiles were removed by evaporation and the residue partitioned between EtOAc and saturated aqueous sodium hydrogen carbonate solution. The resulting precipitate was collected by filtration, washed with water and EtOAc and dried to give the title compound 350 mg, (40%) as a solid. NMR: 3.81-3.96 (m, 2H), 4.77-4.92 (m, 2H), 6.98 (d, 1H), 7.06 (d, 1H), 7.31 (t, 1H), 7.37 (d, 1H), 7.63-7.80 (m, 6H), 7.92 (s, 1H), 8.27 (d, 1H), 9.50 (s, 1H); m/z: 443.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([C:28]#[C:29][CH2:30][O:31][CH2:32][CH2:33][NH:34]C(=O)C(F)(F)F)[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:17][CH2:16]1)([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2]>[NH4+].[OH-]>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([C:28]#[C:29][CH2:30][O:31][CH2:32][CH2:33][NH2:34])[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:17][CH2:16]1)([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: Nc1nc(=O)n([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)cc1C#CCOCCNC(=O)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Product: NCCOCC#Cc1cn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)nc1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The purified protected triphosphate 12 was taken up in concentrated aqueous NH4OH (4 mL) and stirred for 2.5 h at room temperature. The reaction mixture was concentrated to give compound 13 which was formulated with 0.1 M TEAB pH 7.0 to a concentration of 2.6 mM. The concentration and purity of the formulated bulk were confirmed by UV/Vis spectroscopy and analytical ion pair HPLC as described above, respectively. See FIG. 8.
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:25]=[CH:24][C:23](OS(C(F)(F)F)(=O)=O)=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].CN(C=O)C.[CH3:41][C:42]([OH:46])([C:44]#[CH:45])[CH3:43]>CCOCC>[O:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:25]=[CH:24][C:23]([C:45]#[C:44][C:42]([CH3:43])([OH:46])[CH3:41])=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[Si:2]([C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:4])[CH3:3]
Reactant: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: C#CC(C)(C)O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(CC)(c1ccc(C#CC(C)(C)O)c(C)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1
Temperature: 65 °C
Yield: 32.3 %

Procedure:
To an oven-dried, argon-sparged flask was added Pd[PPh3]4 (46 mg) and anhyd Cul (15 mg). To the flask under argon was added a solution of trifluoromethanesulfonic acid 4-{1-[4-(tert-butyl-dimethylsiloxy)-3-methylphenyl]-1-ethyl-propyl}-2-methylphenyl ester (0.42 g, 0.80 mmol) in anhyd DMF (2.5 mL), TEA (0.56 mL, 4.0 mmol) and 2-methyl-3-butyn-2-ol (0.12 mL, 1.2 mmol). After heating at 65° C. for 15 h, the reaction mixture was diluted with Et2O (50 mL), washed with H2O (2×30 mL) and brine, then dried (Na2SO4) and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/Hex, 0:100 to 10:90) to afford the title compound (0.12 g, 32%) as an orange oil. 1H-NMR (CDCl3) δ 7.26 (1.4H, d, J=8.1), 7.01 (1H, d, J=1.8), 6.94 (1H, dd, J=1.8, 8.1), 6.85 (1H, d, J=2.3), 6.80 (1H, dd, J=2.3, 8.3), 6.63 (1H, d, J=8.3), 2.36 (3H, s), 2.14 (3H, s), 2.03 (4H, q, J=7.3), 1.63 (6H, s), 1.01 (9H, s), 0.59 (6H, t, J=7.3), 0.20 (6H, s); Rf=0.10 (silica, 1:9 EtOAct/Hx).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:22]([CH3:24])[CH3:23])(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:19][C:17]1[CH:18]=[C:13]2[CH:12]=[C:11]([C:20]([C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=3)=[CH:21][CH:22]([CH3:24])[CH3:23])[NH:10][C:14]2=[N:15][CH:16]=1
Reactant: CC(C)C=C(c1ccc(S(C)(=O)=O)cc1)c1cc2cc(F)cnc2n1S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C=C(c1ccc(S(C)(=O)=O)cc1)c1cc2cc(F)cnc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
A mixture of 1-benzenesulfonyl-5-fluoro-2-[1-(4-methanesulfonyl-phenyl)-3-methyl-but-1-enyl]-1H-pyrrolo[2,3-b]pyridine (900 mg, 1.8 mmol) and tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 4 ml) was stirred at 25° C. for 20 h. The reaction was quenched with a saturated aqueous ammonium chloride solution (30 mL). The mixture was extracted with ethyl acetate (2×50 mL), washed with a saturated aqueous ammonium chloride solution (3×25 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 5-fluoro-2-[1-(4-methanesulfonyl-phenyl)-3-methyl-but-1-enyl]-1H-pyrrolo[2,3-b]pyridine (600 mg, 92%): LC/MS m/e calcd for C19H19FN2O2S [M+H]+ 359.44, observed 358.8.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Br)=[CH:4][C:3]=1[S:19]([OH:22])(=[O:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].C([NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([NH2:40])[CH:34]=1)(=O)C.Cl>O.C(O)(C)C>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:40][C:35]2[CH:34]=[C:33]([NH2:32])[CH:38]=[CH:37][C:36]=2[CH3:39])=[CH:4][C:3]=1[S:19]([OH:22])(=[O:21])=[O:20]
Reactant: CC(=O)Nc1ccc(C)c(N)c1
Reactant: Nc1c(S(=O)(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(N)cc1Nc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
38.2 Parts 1-amino-4-bromoanthraquinone-2-sulphonic acid are dissolved in 200 parts water/100 parts i-propanol and the pH adjusted to 8.5-9.0 with sodium carbonate. After addition of 18 parts 4-acetylamino-2-aminotoluene the mixture is warmed to 80° C. and treated with 1 part cuprous chloride and 12 parts sodium carbonate. After 4 hours the reaction is over. Finally 25 parts 30% hydrochloric acid are added to the reaction mixture, which is then heated to reflux. After 18 hours the suspension is cooled to room temperature, filtered and washed with 1% hydrochloric acid, to give 1-amino-4-(5'-amino-2'-methylphenylamino)-anthraquinone-2-sulphonic acid.