Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[I-].[CH:12]1([CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:37][O:38][C:39]1[N:44]=[C:43]([C:45]([C:47]2[CH:52]=[CH:51][C:50]([S:53][CH3:54])=[CH:49][CH:48]=2)=O)[CH:42]=[CH:41][C:40]=1[CH3:55].O>O1CCCC1>[CH:12]1(/[CH:17]=[C:45](\[C:43]2[N:44]=[C:39]([O:38][CH3:37])[C:40]([CH3:55])=[CH:41][CH:42]=2)/[C:47]2[CH:52]=[CH:51][C:50]([S:53][CH3:54])=[CH:49][CH:48]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: c1ccc([P+](CC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1nc(C(=O)c2ccc(SC)cc2)ccc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(/C(=C\C2CCCC2)c2ccc(SC)cc2)ccc1C
Yield: 40 %

Procedure:
A solution of lithiumhexamethyldisilazide in tetrahydrofuran (1 M, 5.5 mL) was added to a solution of (cyclopentylmethyl)triphenylphosphonium iodide (1.73 g, 3.66 mmol) in tetrahydrofuran (5 mL) in a nitrogen atmosphere under ice-cooling, and the mixture was stirred under ice-cooling for one hour. A solution of (6-methoxy-5-methylpyridin-2-yl)[4-(methylsulfanyl)phenyl]methanone obtained in Reference Example 1-36 (1.0 g) in tetrahydrofuran (2.5 mL) was added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:hexane=1:9→1:2) to give (Z)-6-{2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-2-methoxy-3-methylpyridine (493 mg, 40%) as a more polar product.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1>O.C(O)(=O)CC>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:1]=[O:3])=[C:9]([OH:13])[CH:8]=1.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][C:12]=1[N:1]=[O:2]
Reactant: COc1cccc(O)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCC(=O)O
Solvent: O
Product: COc1cc(O)ccc1N=O
Product: COc1ccc(N=O)c(O)c1
Reaction time: 1 h

Procedure:
A solution of sodium nitrite (6.9 g, 0.1 mol) dissolved in 15 mL water was added, dropwise, to a solution of 3-methoxyphenol (12.4 g, 0.1 mol) dissolved in propionic acid (100 mL) cooled to -5° to 0° C., at a rate which maintained a temperature of -5° to 0° C. The mixture was stirred for 1 hour to produce a slurry of alkoxy nitrosophenols having a mole ratio of 5-methoxy-2-nitrosophenol to 3-methoxy-4-nitrosophenol of 95:5. Water (85 mL) was added to the slurry and the product was collected by filtration, washed with 60 mL of 50% aqueous propionic acid and then dried to give 10.1 g (66% of theory) of 5-methoxy-2-nitrosophenol which contained approximately 2% of the 3-methoxy-4-nitrosophenol isomer.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a solution of 3-amino-5-bromo pyridine (XXV) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XXVIII) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXIX) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.23 (s, 9H), 8.37 (d, J=2 Hz, 1H), 8.39 (t, J=2 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.58 (brs, 1H); ESIMS found C10H13BrN2O m/z 257.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:11][C:12]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[Cl:19])[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O.[CH3:28][C:29]1(C)C(C)(C)OB(C=C)O1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:20])[N:7]([CH2:11][C:12]1[CH:17]=[C:16]([CH:28]=[CH2:29])[CH:15]=[CH:14][C:13]=1[Cl:19])[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)ccc1Cl)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To a sol. of (5-bromo-2-chloro-benzyl)-cyclopropyl-carbamic acid tert-butyl ester (105 g, 0.292 mol) in DME (800 mL) under N2 at rt was added Pd(PPh3)4 (16.9 g, 14.6 mmol). The mixture was stirred at rt for 30 min, and K2CO3 (40.7 g, 292 mmol), water (350 mL) and 4,4,5,5-tetramethyl-2-vinyl-[1,3,2]dioxaborolane (52.0 mL, 292 mmol) were added. The mixture was heated to reflux for 3 h. The mixture was allowed to cool to rt, and water (500 mL) was added. The mixture was extracted with Et2O (4×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 9:1) yielded the title compound (70.9 g, 79%). LC-MS: tR=1.10 min; ES+: 293.38.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH2:31]([O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)[CH2:32][CH2:33][CH3:34]>>[CH2:31]([O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:44])=[O:43])=[CH:38][CH:37]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCOc1ccc(S(=O)(=O)Nc2ccc(N3CCNCC3)cc2NS(=O)(=O)c2ccccc2)cc1

Procedure:
4-Butoxy-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 4-n-butoxybenzenesulfonylchloride (59 mg, 0.239 mmol) according to general method 3 to give 70 mg of a purple solid. MS (posES-FIA) m/z=Found: 545.2; Calcd 545.18; 1H-NMR δ 7.73–7.45 (m, 7H), 6.95–6.91 (m, 2H), 6.72–6.70 (m, 1H), 4.00 (t, 2H), 3.29–3.24 (m, 8H), 1.79–1.70 (m, 2H), 1.55–1.43 (m, 2H), 0.97 (t, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:18]([F:27])([F:26])[C:19]([O:21]C(C)(C)C)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:11]=1)=[O:4].[S:35]1[CH:39]=[C:38]([CH:40]=O)[N:37]=[CH:36]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:27][C:18]([F:26])([C:8]1[CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH:11]=[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:40][C:38]2[N:37]=[CH:36][S:35][CH:39]=2)[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=1)[C:19]([OH:21])=[O:20]
Reactant: CC(C)(C)OC(=O)C(F)(F)c1cc(NC(=O)[C@@H](N)Cc2ccccc2)cc(-c2ccncc2)c1
Reactant: O=Cc1cscn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Nc1cc(-c2ccncc2)cc(C(F)(F)C(=O)O)c1)[C@H](Cc1ccccc1)NCc1cscn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of (S)-tert-butyl 2-(3-(2-amino-3-phenylpropanamido)-5-(pyridin-4-yl)phenyl)-2,2-difluoroacetate 52.F (300 mg, 0.64 mmol) in DCM (5 mL) was added thiazole-4-carbaldehyde (73 mg, 0.64 mmol). The mixture was stirred for 1 h at room temperature, then acetic acid (30 μL, 0.64 mmol) and sodium triacetoxyborohydride (408 mg, 1.93 mmol) were added and the mixture stirred at room temperature for an additional 2 hours. The mixture was then concentrated and the residue was stirred in THF (5 mL) and concentrated HCl (5 mL) at 50° C. overnight. The mixture was then concentrated and the crude product purified by reverse phase chromatography (0-100% CH3CN/water+0.5% TFA) to afford (S)-2,2-difluoro-2-(3-(3-phenyl-2-(thiazol-4-ylmethylamino)propanamido)-5-(pyridin-4-yl)phenyl)acetic acid 52 as a white solid (140 mg, 43% yield). LCMS ESI (pos.) m/e: 509.0. (M+1). 1H NMR (500 MHz, MeOH-D4) δ ppm 9.14 (d, J=1.96 Hz, 1H), 8.81-8.87 (m, 2H), 8.16 (t, J=1.83 Hz, 1H), 8.12-8.15 (m, 2H), 7.88 (s, 1H), 7.81 (d, J=1.96 Hz, 1H), 7.72 (s, 1H), 7.24-7.37 (m, 5H), 4.46-4.59 (m, 2H), 4.27 (dd, J=9.29, 5.87 Hz, 1H), 3.40-3.51 (m, 1H), 3.27 (dd, J=13.45, 9.29 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C:3](=[O:23])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12]C(=O)OCC2C=CC=CC=2)[CH2:7][CH2:6]1.C(O)(=O)C>[Pd].C(O)C>[NH2:12][CH2:11][CH:8]1[CH2:7][CH2:6][N:5]([CH2:4][C:3](=[O:23])[C:2]([CH3:24])([CH3:1])[CH3:25])[CH2:10][CH2:9]1
Reactant: CC(C)(C)C(=O)CN1CCC(CNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)CN1CCC(CN)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 45.9 %

Procedure:
A mixture of benzyl [1-(3,3-dimethyl-2-oxobutyl)piperidin-4-yl]methylcarbamate (Step 1, 9.6 g, 27.7 mmol), 5% palladium on carbon (1.2 g) and acetic acid (4 mL) in ethanol (70 mL) was stirred at room temperature for 23 h under hydrogen atmosphere. Palladium on carbon was removed by filtration through a pad of Celite and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with aqueous ammonia and extracted with ethyl acetate (5×50 mL). After dried over magnesium sulfate, removal of solvent gave the title compound (2.7 g, 46%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH:13]S(C(C)(C)C)=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO.C(=O)([O-])[O-].[K+].[K+]>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH2:13])[C:9]([F:10])([F:11])[F:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(=O)NC(c1ccc(Br)nc1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: NC(c1ccc(Br)nc1)C(F)(F)F

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [1-(6-bromo-pyridin-3-yl)-2,2,2-trifluoro-ethyl]-amide (1.17 g, 3.26 mmol) in methanol (15 mL) was added a 4 N solution of HCl in dioxane (2 mL, 8.0 mmol). The reaction was monitored by TLC (ethyl acetate-hexanes 3:7). The mixture was diluted with saturated aqueous potassium carbonate and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (3×15 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with ethyl acetate-hexanes (1:9, then 2:8) to afford the title compound as a clear oil.
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([C:8](Cl)=[O:9])=[CH:5][CH:4]=1)#[N:2].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:14]=1.CCN(C(C)C)C(C)C>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:8]([C:6]2[O:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:9])=[C:15]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:14]=1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: COc1ccc(N)c(N2CCCCC2)c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2ccc(C#N)o2)c(N2CCCCC2)c1
Yield: 60 %

Procedure:
Using a procedure similar to Example 1, step (e), 5-cyano-furan-2-carbonyl chloride (66 mg, 0.43 mmol) was allowed to react with 4-methoxy-2-piperidin-1-yl-phenylamine (67 mg, 0.32 mmol, as prepared in the previous step) in the presence of DIEA (164 μL, 0.940 mmol) for 2 h to afford 62 mg (60%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 9.49 (br s, 1H) 8.35 (d, 1H, J=8.9 Hz), 7.27-7.22 (m, 1H), 6.76 (d, 1H, J=2.7 Hz), 6.71 (dd, 1H, J=2.8, 8.9 Hz), 3.81 (s, 3H), 2.85-2.83 (m, 4H), 1.84-1.78 (m, 4H), 1.66-1.65 (m, 2H); Mass spectrum (ESI, m/z): Calcd. for C18H19N3O3, 326.1 (M+H), found 326.1.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:27][CH3:28])[C:4]1[CH:5]=[C:6]([CH:11]([C:14]2[C:19]([CH:20]([CH3:22])[CH3:21])=[C:18]([O:23][CH3:24])[N:17]=[C:16]([O:25][CH3:26])[N:15]=2)C#N)[CH:7]=[C:8]([CH3:10])[CH:9]=1.[H-].[Na+].CN(C=[O:35])C>>[CH3:1][O:2][CH:3]([O:27][CH3:28])[C:4]1[CH:5]=[C:6]([C:11]([C:14]2[C:19]([CH:20]([CH3:22])[CH3:21])=[C:18]([O:23][CH3:24])[N:17]=[C:16]([O:25][CH3:26])[N:15]=2)=[O:35])[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: CN(C)C=O
Reactant: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(C)cc(C(OC)OC)c2)n1
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(C(OC)OC)c2)n1
Reaction time: 0.33 h
Yield: 98 %

Procedure:
To a stirred solution of (3-dimethoxymethyl-5-methyl-phenyl)-(5-isopropyl-2,6-dimethoxy-pyrimidin-4-yl)-acetonitrile (3.4 g, 8.8 mmol) in anhydrous DMF (36 ml) at room temperature under nitrogen atmosphere, was added 60% sodium hydride (0.423 g, 10.6 mmol). After 20 min., oxygen was bubbled into the mixture for 3 hr. The mixture was then partitioned between ether and water, The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:4)) to afford 3.26 g (98%) of a pale yellow solid. m.p. 86-88° C.; 1H NMR (300 MHz, CDCl3) δ 1.22 (6H, d, J=6.3 Hz), 2.41 (3H, s), 2.81 (1H, m), 3.31 (6H, s), 3.93 (3H, s), 4.06 (3H, s), 5.36 (1H, s), 7.53 (1H, s), 7.64 (1H, s), 7.71 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4]([CH3:10])=[N:3]1.C([Li])CCC.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([Sn:20]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:16][CH2:17][CH2:18][CH3:19])[S:9][C:5]=2[C:4]([CH3:10])=[N:3]1
Reactant: Cc1nn(C)c2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2c(s1)c(C)nn2C
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a cold (−78° C.) mixture of 1,3-dimethyl-1H-thieno[3,2-c]pyrazole (400 mg, 2.63 mmol) and THF (15 mL) under a nitrogen atmosphere was added n-butyllithium (1.156 mL, 2.89 mmol) dropwise. The reaction mixture was stirred at −78° C. for 60 minutes. Tributylchlorostannane (0.855 mL, 3.15 mmol) was added, and the reaction mixture was stirred at −78° C. for 60 minutes and then warmed to room temperature with stirring over a period of 1 hour. The reaction mixture was quenched with brine (15 mL) and extracted with EtOAc (2×25 mL). The organic layers were combined, dried over sodium sulfate, and evaporated. The resulting residue was purified by normal-phase silica gel column (80 g) chromatography, eluting with a gradient of 0-100% hexane and EtOAc. The pure product fractions were combined and evaporated to give the title compound as a clear oil (1.060 g, 91%). 1H NMR (400 MHz, CDCl3) δ ppm 0.77-0.98 (m, 9H), 1.04-1.20 (m, 6H), 1.25-1.47 (m, 6H), 1.49-1.70 (m, 6H), 2.41 (s, 3H), 3.94 (s, 3H), 6.82 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C19H34N2SSn, 443. found, 443.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]1[CH2:17][C:18]([O:20]C)=[O:19].[Li+].[OH-].O.Cl>C1COCC1.O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13]([F:15])([F:14])[F:16])[CH:8]=2)[N:3]1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)Cn1c(=O)ccc2cc(OC(F)(F)F)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1c(=O)ccc2cc(OC(F)(F)F)ccc21
Reaction time: 8 h

Procedure:
To a stirring solution of methyl 2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetate (1.2 mmol) in THF/water (2:1) was added LiOH. H2O (8.1 mmol). The resulting mixture was stirred overnight. The crude product mixture was slowly acidified with 1N HCl solution and then extracted with EtOAc. The organic phase was separated, dried (MgSO4), filtered and concentrated under vacuum to give 2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid. Retention time (min)=1.783, method [1], MS(ESI) 288.1 (M+H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][NH:29][CH2:30][CH2:31][CH3:32]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:29]([CH3:28])[CH2:30][CH2:31][CH3:32])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCCNC
Solvent: CC#N
Product: CCCN(C)C[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), N-methyl-propan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 333 (M+, 0.3), 304 (4), 87 (6), 86 (bp), 84 (7), 58 (10).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH:31]=[C:30]([C:35]2[CH:36]=[C:37]4[C:57](=[CH:58][CH:59]=2)[C:41]2[NH:42][C:43]([C@@H:45]5[CH2:49][CH2:48][CH2:47][N:46]5C(OC(C)(C)C)=O)=[N:44][C:40]=2[CH:39]=[CH:38]4)[CH:29]=[CH:28]3)=[CH:23][N:24]=1)=O)(C)(C)C>C(Cl)Cl>[NH:46]1[CH2:47][CH2:48][CH2:49][C@H:45]1[C:43]1[NH:42][C:41]2[C:57]3[C:37]([CH:38]=[CH:39][C:40]=2[N:44]=1)=[CH:36][C:35]([C:30]1[CH:29]=[CH:28][C:27]2[C:32](=[CH:33][CH:34]=[C:25]([C:22]4[NH:21][C:20]([C@@H:16]5[CH2:17][CH2:18][CH2:19][NH:15]5)=[N:24][CH:23]=4)[CH:26]=2)[CH:31]=1)=[CH:59][CH:58]=3
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]c65)c4)ccc3c2)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2cc(-c3cnc([C@@H]4CCCN4)[nH]3)ccc2cc1-c1ccc2c(ccc3nc([C@@H]4CCCN4)[nH]c32)c1
Reaction time: 2 h
Yield: 102 %

Procedure:
TFA (2 mL, 26.0 mmol) was added in one portion to a stirred solution of (S)-tert-butyl 2-(7-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (137 mg) in CH2Cl2 (10 mL) at room temperature. The mixture was stirred for 2 h at room temp. and then the solvents were removed in vacuo. The residue was taken up in 50% methanol/CH2Cl2 and filtered through an MCX cartridge (Strata XC). The cartridge was washed with methanol and the compound was eluted with a solution of NH3 in methanol (2M). The appropriate fractions were concentrated in vacuo to afford 2-((S)-pyrrolidin-2-yl)-7-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazole (98 mg, 0.20 mmol) as orange solid. LC-MS retention time 1.245 min; m/z 499.30 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.59 (d, J=8.5 Hz, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 8.13 (dd, J=8.6, 1.8 Hz, 1H), 8.01-8.10 (m, 3H), 7.90-7.98 (m, 2H), 7.87 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 5.18 (t, J=7.9 Hz, 1H), 5.05 (t, J=8.1 Hz, 1H), 3.63-3.72 (m, 1H), 3.52-3.63 (m, 3H), 2.61-2.77 (m, 2H), 2.45-2.58 (m, 2H), 2.33-2.43 (m, 2H), 2.20-2.33 (m, 2H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]1[CH2:11][S:8](=[O:10])(=[O:9])[O:7][CH2:6]1>O.CC(C)=O>[N:1]([CH2:6][CH2:5][CH2:11][S:8]([OH:10])(=[O:9])=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S1(=O)CCCO1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a stirred solution of sodium azide (3.5 g, 50 mmol) in water (25 mL) was added a solution of 1,3-propane sultone (6.1 g, 50 mmol) in acetone (25 mL). The reaction mixture was stirred at room temperature for 24 h then concentrated to dryness. The resulting solid was suspended in diethyl ether (100 mL) and stirred at reflux for 1 h. The suspension was cooled to room temperature and the solid was collected by filtration, washed with acetone and diethyl ether, and dried under vacuum, affording of 3-azido-1-propanesulfonic acid (7.6 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](O)[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.C1(C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:26]>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:26])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)N1Cc2nc(N)nc(O)c2C1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCOC(=O)N1Cc2nc(N)nc(Cl)c2C1
Yield: 57.1 %

Procedure:
Intermediate (h) (11 g, 49 mmol) was azeotroped×2 with toluene. Anhydrous acetonitrile (250 mL) and POCl3 (25 mL, 270 mmol) were added and the mixture was refluxed for about 2.5 h. Additional POCl3 (50 mL) was added and the mixture was refluxed for an additional 2 h. The volatile components were concentrated under vacuum at 40° C. to give a red solution. A minimum amount of dry acetonitrile was added until the solution was readily transferable whereupon it was poured onto ice in a large beaker. The flask was further rinsed with a small amount of acetonitrile which was added to the ice. Water (about 50 mL) was added to the ice mixture to help it with stirring. Concentrated NH4OH (25 mL) was added slowly with stirring until the ice slurry mixture was strongly basic, then 50% aqueous NaOH (25 mL) was also added to the still stirring slurry of ice. Additional ice was added. After about 5 minutes stirring as ice slurry, EtOAc was added. After stirring in the beaker for several more minutes, water was added to help melt the ice. The mixture was poured into a separatory funnel and the layers were allowed to partition. The aqueous layer was extracted with EtOAc×3. The combined EtOAc extracts were washed ×2 with saturated aqueous KHSO4, ×2 with saturated aqueous NaHCO3, ×1 with brine, dried over Na2SO4, filtered and evaporated to afford a pale pink powder which was triturated with ethyl acetate to give compound I(C) as pale pink solids (6.8 g, 28 mmol) in 57% yield. HPLC/LCMS purity was greater than 90%. 1H NMR (400 MHz, DMSO-D6) δ ppm 7.20 (s, 2H), 4.48 (s, 2H), 4.45 (s, 2H), 4.17-4.08 (m, 2H), 1.24 (t, 3H). LCMS (M+H)+: 243.2, 245.2.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[C:34](=O)[NH:33][C:32]([NH:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[N:43]=[CH:42][CH:41]=[CH:40]3)=[C:31]([C:47]#[N:48])[CH:30]=1>O1CCOCC1>[Cl:1][C:34]1[C:29]([F:28])=[CH:30][C:31]([C:47]#[N:48])=[C:32]([NH:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[N:43]=[CH:42][CH:41]=[CH:40]3)[N:33]=1
Reactant: N#Cc1cc(F)c(=O)[nH]c1Nc1ccc2ncccc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1cc(F)c(Cl)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
A 1,4-dioxane (100 ml) solution containing N-chlorosuccinimide (4.15 g) was added dropwise to a 1,4-dioxane (50 ml) solution containing triphenylphosphine (8.58 g) at 50° C., followed by stirring for 30 minutes. 5-fluoro-6-oxo-2-(quinolin-6-ylamino)-1,6-dihydropyridin-3-carbonitrile (2.61 g) was added to the reaction mixture, followed by stirring at 70° C. for 3 hours. The reaction mixture was cooled to room temperature. Then solid matter was collected by filtration and was washed with tetrahydrofuran, and a gray solid of 6-chloro-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile (2.34 g) was thus obtained.