Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15])=[O:6].C([C:29]1[C:30]([N:36]=[CH:37][N:38]([CH3:40])C)=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1)#N.NC1C=C(C=CC=1SC1C=CC(O)=CC=1)C(NC1C=CC(Br)=CC=1)=O>>[Br:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:16]=[CH:17][C:18]([S:19][C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[C:2]([NH:1][C:40]2[C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[N:31][C:30]=3[N:36]=[CH:37][N:38]=2)[CH:3]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc(C(=O)NCc2ccccc2Br)ccc1Sc1ccc(O)cc1
Agent: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(C(=O)NCc4ccccc4Br)ccc3Sc3ccc(O)cc3)ncnc2n1
Yield: 71 %

Procedure:
The product of Example 31A was reacted with the product of Example 9B using the procedure of Example 22C substituting the product of Example 31A for the product of Example 22B and substituting the product of Example 9B for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (60 mg, 71%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.68 (s, 3 H) 4.48 (d, J=5.52 Hz, 2 H) 6.84 (d, J=8.82 Hz, 2 H) 6.87-6.96 (m, 1 H) 7.16-7.25 (m, 1 H) 7.25-7.40 (m, 4 H) 7.56 (d, J=8.09 Hz, 1 H) 7.61 (d, J=8.82 Hz, 1 H) 7.76 (d, J=8.82 Hz, 1 H) 7.93 (s, 1 H) 8.58 (s, 1 H) 8.74-8.85 (m, 1 H) 8.94-9.21 (m, 1 H) 9.94 (s, 1 H) 10.16 (s, 1 H); MS (ESI+) m/z 572/574 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.[OH-].[Na+]>COCCOC.CCOC(C)=O.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>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=3)=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)=[CH:21][CH:20]=1
Reactant: Cc1cccc(-c2nn3ccccc3c2Br)n1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1cccc(-c2nn3ccccc3c2-c2ccc(F)cc2)n1
Yield: 60.1 %

Procedure:
A solution of 3-bromo-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine (0.25 g, 0.9 mmol) and p-fluorophenyl-boronic acid (0.15 g, 1.04 mmol), in DME (10 mL) is purged with argon. The solution is treated with NaOH (0.07 g, 1.7 mmol) and (PPh3)4Pd (0.05 g, 0.04 mmol) then heated at reflux overnight. The reaction is then cooled, diluted in EtOAc, and washed with water and brine. The organic solution is dried over MgSO4 and the solvent removed in vacuo. The residue is purified by silica gel column chromatography using a mixture of hexanes/EtOAc to afford 0.164 g (62%) of desired product as a white solid. UV (95% EtOH) λmax 248 nm (ε 20386). TOF MS ES+ exact mass calculated for C19H14FN3 (p+1): m/z=304.1250. Found: 304.1249. Anal. Calcd for C19H14FN3: C, 75.23; H, 4.65; N, 13.85. Found: C, 75.10; H, 4.76; N, 13.70.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]([NH:10][CH:11]([CH3:14])[CH2:12][CH3:13])=[N:7][C:8]=1[CH3:9])#[N:2].[Se](=O)=[O:21]>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]([NH:10][CH:11]([CH3:14])[CH2:12][CH3:13])=[N:7][C:8]=1[CH:9]=[O:21])#[N:2]
Reactant: CCOC(=O)c1cc(C#N)c(C)nc1NC(C)CC
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C#N)c(C=O)nc1NC(C)CC

Procedure:
26.1 g of 5-cyano-6-methyl-2-[(1-methylpropyl)amino]-3-pyridine-carboxylic acid, ethyl ester (0.1 mol) and 13 g of selenium dioxide are refluxed together in dioxane for 24 hours. After this time the selenium is filtered off and the solvent removed in vacuo. The resulting oily residue is crystallized with ether. Yield 19 g (69%); m.p. 37°-38° C. (methanol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([O:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][CH2:6][CH3:7].CS(C)=O.O.Cl.[CH3:34][CH2:35]OCC>>[C:10]1([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][C:34]#[CH:35])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCC(CCCl)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOCC
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: C#CCCC(CCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a stirred solution of 32.2 g. (85 mmoles) of 1-chloro-3-triphenylmethoxyhexane (Example 906) in 25 ml. of dimethylsulfoxide (DMSO) is added a solution of 9.4 g. (102 mmoles) of lithium acetylide-ethylene diamine complex in 60 ml. of DMSO during 10 minutes while maintaining a temperature of 25°-30° C. After 3.5 hours the mixture is diluted with ether and treated successively with water and 4N hydrochloric acid while cooling in an ice bath. The phases are separated, and the aqueous phase is extracted with ether-petroleum ether. The combined extracts are washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The product is then purified by column chromatography of the residue on Florisil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].[Li+].[BH4-].CO>CCOCC>[Cl:1][C:2]1[CH:12]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[O:13][CH2:14][C:15]([F:16])([F:17])[F:18]
Reactant: CCOC(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: OCc1cnc(OCC(F)(F)F)c(Cl)c1
Temperature: 40 °C
Yield: 98.6 %

Procedure:
To a solution of ethyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (7.51 g, 26.5 mmol) in Et2O (200 mL) was added LiBH4 (0.865 g, 39.7 mmol), followed by drop wise addition of methanol (1.611 ml, 39.7 mmol). The reaction was refluxed at 40° C. for one hour. The reaction mixture was then cooled to 0° C., and quenched with HCl (1M) until pH=2 for aqueous layer. The phases were separated and the aqueous layer was extracted with DCM (3×200 mL). The organic was then dried (Na2SO4) and concentrated under reduced pressure to give final crude product (6.31 g). LCMS m/z 242.1 (M+H)+, Rt 0.77 min.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18]Cl)[N:12]=[CH:11][N:10]=[C:9]2[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[CH:28])[CH:22]=1.[C:29]([O-:32])(=[O:31])[CH3:30]>CN(C=O)C>[C:29]([O:32][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:32][C:29](=[O:31])[CH3:30])[N:12]=[CH:11][N:10]=[C:9]2[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[CH:28])[CH:22]=1)(=[O:31])[CH3:30]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCCl)c(OCCCl)cc23)c1
Reactant: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC(C)=O)c(OCCOC(C)=O)cc23)c1
Yield: 135.2 %

Procedure:
The title product of Example 29 (200 mg, 0.456 mmol) was treated with cesuim acetate (1.75 g, 9.12 mmol) in DMF (3 mL) at 120° C. under an atmosphere of N2 for 16 hours. The reaction mixture was partitioned between brine and CHCl3, and the organic extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford an oil (277 mg) which was recrystallized from CH2 Cl2 /hexane. (184 mg; 90%; M.P. 137°-138° C.; LC-MS: 450 (MH+); anal. RP18-HPLC RT: 4.64 min.).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:11])[C:8](Cl)=[O:9].[C:12]1([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:11])[C:8]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:13][CH:14]=1)=[O:9]
Reactant: COC(=O)C(=O)Cl
Reactant: c1ccc2c(OCCN3CCOCC3)cccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(OCCN2CCOCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.2 %

Procedure:
To a round bottom flask was added CH2Cl2 (100 mL) followed by the addition of AlCl3 (2.2 g, 16.3 mmol). The suspension was stirred 5 min at room temperature, methylchloroglyoxylate (1.66 mL, 17.88 mmol) was added and stirred an additional 5 min, followed by the addition of 11 (0.841 g, 3.27 mmol). The mixture was stirred at room temperature overnight, quenched with water, neutralized with NaHCO3 and extracted with EtOAc three times. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the solvent removed leaving a brown oil. The material was purified by column chromatography (0-5% MeOH/CH2Cl2) providing 1.08 g of 12 (97%) as a yellow solid. LC-MS: Calculated mass=343. Observed mass=344.
Reaction SMILES: [OH-].[Na+].COC(=O)CN(CC(OC)=O)[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:10][CH:9]=1.[C:34]([CH2:37][N:38](C1C=CC(CCCCCCCCCCCCCC)=CC=1)[CH2:39][C:40]([OH:42])=[O:41])([OH:36])=[O:35]>CO>[C:34]([CH2:37][N:38]([C:9]1[CH:8]=[CH:13][CH:12]=[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:10]=1)[CH2:39][C:40]([OH:42])=[O:41])([OH:36])=[O:35]
Reactant: CCCCCCCCCCCCCCc1ccc(N(CC(=O)O)CC(=O)O)cc1
Reactant: CCCCCCCCCCCCCCc1ccc(N(CC(=O)OC)CC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCc1cccc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 72 h

Procedure:
A mixture of 1.0 g (3.45 mmol) of 4-tetradecylphenyl aniline (Aldrich Chemical Company), 5.0 ml (0.052 mol) of methyl bromoacetate, 0.95 g (6.9 mmol) of potassium carbonate and 0.5 g (3.45 mmol) of sodium iodide in 15 ml of DMF was stirred and heated at 100° for 45 hours. The solvent was removed at reduced pressure and water was added to the residue. The product was extracted with ethyl acetate and the extract was washed with sodium bisulfite solution, dried and concentrated. The residue was purified by chromatography on silica gel using 25% ethyl acetate-hexane to give 0.7 g of N-(2-methoxy-2-oxoethyl)-N-(4-tetradecylphenyl)glycine methyl ester. This dimethyl ester was hydrolyzed by treatment with 1.5 ml of 6N NaOH in 50 ml of methanol. The mixture was warmed briefly to dissolve the ester and then was kept at room temperature for 3 days. The solvent was removed at reduced pressure and the residue was acidified to pH 2. The product was extracted with ethyl acetate and the dried extract was concentrated at reduced pressure to a solid which was recrystallized from methanol-water to give 0.26 g, mp 160°-165°, of N-(carboxymethyl)-N-(4-tetradecylphenyl)glycine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][CH2:26][C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2)=[O:23].Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][CH2:26][C:27]12[CH2:34][CH:33]3[CH2:35][CH:29]([CH2:30][CH:31]([CH2:32]3)[CH2:36]1)[CH2:28]2)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)c(C(=O)NCCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NCCC12CC3CC(CC(C3)C1)C2)c1cc(N2CCCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.2 %

Procedure:
4-[4-Chloro-3-[[(2-tricyclo[3.3.1.13,7]dec-1-ylethyl)amino]carbonyl]phenyl]-hexahydro-1H-1,4-diazepine-1-carboxylic acid, 1,1-dimethylethyl ester (0.053 g, Example 74a) was dissolved in methanol (5 ml) and hydrochloric acid (0.5 ml from a 4N solution in dioxane) was added. After stirring at room temperature for 14 h, the mixture was evaporated to ¾ original volume under reduced pressure. Diethyl ether was gradually added to the solution and the resulting precipitate was collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound as a cream solid (0.017 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)C[CH2:22]1.F[P-](F)(F)(F)(F)F>CCO.CN(C1C=CN=CC=1)C>[CH2:21]([O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-(4-iodo-phenyl)-propionic acid (3 g) in anh. EtOH (38 mL) was added DMAP (187 mg) and PyBOP (6 g). The reaction mixture was stirred on at RT and partitioned between EA and water. The org. phase was separated, washed with 10% aq. citric acid and sat. aq. NaHCO3, dried (Na2SO4) and evaporated off. The resulting crude material was purified by CC (Hept/EA 1/0 to 0/1) to afford the title compound as a white solid (3 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CCN(CC)CC.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(Cl)Cl>[N:21]1([S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a suspension of 4-acetylbenzenesulfonyl chloride (5.5 g, 25 mmol) in CH2Cl2 (75 mL) and Et3N (2 equiv, 7.0 mL, 50 mmol) was added morpholine (1.5 equiv, 3.3 mL, 38 mmol) dropwise. The mixture was stirred at room temperature for 30 min. The mixture was then diluted with CH2Cl2 (100 mL) and washed with 5% HCl (2×50 mL), water (50 mL), and then brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to afford crude 1-[4-(morpholine-4-sulfonyl)phenyl]ethanone (2) (4.78 g, 18 mmol, 71%): HPLC Retention Time; 5.82 min. (Method B) M+1, 270.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1.C(O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC1=CC(=O)NC1
Reactant: OCc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C=C(OCc2ccccc2)CN1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
5.7 g of 4-methoxy-3-pyrrolin-2-one and 10.8 g of benzyl alcohol were mixed with 0.4 g of methane sulfonic acid and stirred for 24 hours at 80° C. and 20 mbars. Then the reaction solution was mixed with 50 ml of ice water and 100 ml of methylene chloride and neutralized with 4 ml of saturated NaHCO3 solution. The aqueous phase was extracted twice more with 50 ml each of methylene chloride. After drying of the organic phase over Na2SO4 and distilling off of the solvent, the residue was mixed with 150 ml of ice water, heated to 100° C. and 100 ml of water-benzyl alcohol was azeotropically distilled off. The crystals precipitated during the cooling were recrystallized hot from 50 ml of toluene. 6.7 g of white, crystalline product with a melting point of 147° to 148° was obtained. For the product:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[N:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=1.[O:22]=[C:23]1[CH2:28][S:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(Cl)Cl.CCO>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[N:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH2:33][C:31]2[CH:30]=[CH:29][C:26]3[S:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=3[N:32]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc2nccc(-c3ccc(CCN)cn3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2nccc(-c3ccc(CCNCc4ccc5c(n4)NC(=O)CS5)cn3)c2n1
Reaction time: 24 h
Yield: 30.2 %

Procedure:
To a stirred solution of 2-[6-(6-methoxy[1,5]naphthyridin-4-yl)pyridin-3-yl]ethylamine (0.94 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (0.18 g, 0.94 mmole) and Na2SO4 (500 mg). After 24 h, the reaction contents were concentrated and dried under high vacuum. To a stirred solution of the crude imine in dry EtOH (25 mL) at RT was added NaBH4 (36 mg, 0.94 mmole). After 24 h, the reaction solution was concentrated under vacuum and to the residue was added 1M HCl (5 mL) and EtOAc (50 mL). After stirring for 1 h, 6M NaOH (1 mL) was added and the organic layer was separated, dried (Na2SO4) and concentrated. Purification on reverse-phase HPLC (CH3CN/H2O, 10-90%) afforded the title compound (0.13 g, 30%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.89 (br s, 1H), 9.15 (m, 1H), 8.90 (m, 1H), 8.57 (d, J=9.1 Hz, 1H), 8.45 (d, J=9.1 Hz, 1H), 8.20 (m, 2H), 7.51 (m, 1H), 7.22 (d, J=9.1 Hz, 1H), 6.88 (d, J=7.9 Hz, 1H), 4.24 (m, 2H), 4.02 (s, 3H), 3.55 (m, 2H), 3.41 (m, 2H), 3.30 (s, 2H). LC-MS (ES) m/e 459 (M+H)+.
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]1[C:11]([C:12](=[O:14])[CH3:13])=[C:10]([F:15])[C:9]([F:16])=[C:8]([F:17])[C:7]=1[F:18].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>C(O)C.CCOCC>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:13][C:12]([C:11]2[C:6]([F:5])=[C:7]([F:18])[C:8]([F:17])=[C:9]([F:16])[C:10]=2[F:15])=[O:14])=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)c1c(F)c(F)c(F)c(F)c1F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: O=C(C=Cc1ccc(F)cc1)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.6 %

Procedure:
A solution of sodium ethoxide (21% in EtOH, 0.32 gm, 4.76 mmol) was added to a mixture of 1-(pentafluorophenyl)-1-ethanone (5.91 gm, 47.6 mmol, Aldrich) and 4-fluorobenzaldehyde (10.00 gm, 47.6 mmol) stirring in ethanol (100 ml) under argon. The solution was allowed to stir at room temperature for 18 hours, then EtOH was evaporated to afford a yellowish, oily solid. The solid was redissolved in ether, washed with water and brine, then dried over MgSO4, filtered and concentrated to give a yellow residue. The residue was purified by flash chromatography on Merck silica gel in 5% EtOAc/hexane. Fractions containing the product were combined and concentrated to a yellow solid. The solid was recrystallized from hexane to afford the title compound as large yellow crystals (8.220 gm, 52%).
Reaction SMILES: C[O:2][C:3](=[O:44])[CH:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](S(C1C=CC=CC=1)(=O)=O)[CH:11]=[C:10]2[C:25]1[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:28]=[C:27]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:26]=1[O:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH3:6].[OH-].[Na+]>CO.O1CCOCC1.Cl>[CH2:40]([O:39][C:26]1[C:27]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:28][C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:30][C:25]=1[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:5]([CH3:6])=[CH:4][C:3]([OH:44])=[O:2])[CH:8]=2)[NH:12][CH:11]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCOc1c(-c2cn(S(=O)(=O)c3ccccc3)c3ccc(C(C)=CC(=O)OC)cc23)cc(C(C)(C)C)cc1C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1c(-c2c[nH]c3ccc(C(C)=CC(=O)O)cc23)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 115.5 %

Procedure:
3-[1-Benzenesulfonyl-3-(2-butoxy-3,5-di-tert-butyl-phenyl)-1H-indol-5-yl]-but-2-enoic acid methyl ester (187 mg, 0.3 mmol) was dissolved in methanol (2 mL)/dioxane (3.5 mL) and treated with 1N NaOH (2 mL) at 60° C. for 4 h. Diluted with 1N HCl (3 mL) and extracted with ethyl acetate (3×10 mL). The combined organic portions were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to provide 160 mg of an orange solid. The material was purified using radial chromatography (eluet: hexane/ethyl acetate gradient) to provide 85 mg (62%) of a yellow foam. 1H NMR (250 MHz, CDCl3): δ 8.24 (bs, 1H), 7.88 (s, 1H), 7.40-7.35 (m, 3H), 7.28 (d, 2H), 6.18 (s, 1H), 3.37 (t, 2H, J=6.5), 2.61 (s, 3H), 1.41 (s, 9H), 1.28 (s, 9H), 1.19-0.98 (m, 4H), 0.56 (t, 3H, J=7.2). MS [EI+] 462 M+H)+, [EI−] 460 (M−H)+. Anal. Calcd for C30H39NO3: C, 78.05; H, 8.52; N, 3.03. Found: C, 78.10; H, 8.30; N, 3.02.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]([NH2:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C(N(CC)CC)C>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([N:4]([CH2:5][CH:6]([NH:17][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2][NH:1][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCNCC(N)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NCCN(CC(Cc2ccc([N+](=O)[O-])cc2)NS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
Intermediate XXII is prepared based on the synthetic approach shown in Scheme 2. N1-(2-aminoethyl)-3-(4-nitrophenyl)propane-1,2-diamine (XX) is protected using tosyl chloride and triethylamine to afford tritosylated compound 4-methyl-N-(2-(4-methylphenylsulfonamido)-3-(4-nitrophenyl)propyl)-N-(2-(4-methylphenylsulfonamido)ethyl)benzenesulfonamide (XXI). Deprotonation of (XXI) with sodium ethoxide in ethanol produces a disodium salt of compound (XXI), compound (XXII). Compound (XX) is produced according to the method of Corson et al. (Corson, D. T.; Meares, C. F. Bioconjugate Chem. 2000, 11, 292-299, the disclosure of which is incorporated herein by reference).