Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:10]([C:14]1[N:15]([CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][N:28]3[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]#[N:40])[C:16]([C:20]([OH:22])=[O:21])=[C:17]([Cl:19])[N:18]=1)[CH2:11][CH2:12][CH3:13]>CN(C)C=O.C(OCC)(=O)C>[CH2:10]([C:14]1[N:15]([CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][N:28]3[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]#[N:40])[C:16]([C:20]([O:22][CH2:1][CH3:2])=[O:21])=[C:17]([Cl:19])[N:18]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCI
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1cccc2c1ccn2-c1ccccc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C(=O)OCC)n1Cc1cccc2c1ccn2-c1ccccc1C#N
Reaction time: 1.5 h

Procedure:
Ethyl iodide (561.5 mg, 3.60 mmol) and cesium carbonate (1.5g, 4.5 mmol) were added to a solution of 2-butyl-4-chloro-1-[[1-(2-cyanophenyl)-1H-indol-4-yl]methyl]-1H-imidazole-5carboxylic acid (779.2 mg, 1.80 mmol, prepared as described in part C of Example 9) in dimethylformamide (3.72 ml). After 1.5 hours at room temperature, the reaction was diluted with ethyl acetate and filtered to remove the cesium carbonate. The ethyl acetate was washed with pH=4 buffer (2×20 ml), pH=7 buffer (2×25 ml), saturated sodium chloride (20 mL) and dried over anhydrous magnesium sulfate, filtered and concentrated to a yellow oil (890 mg). Purification by flash chromatography (83 g Merck silica gel, 8:2 hexane/ethyl acetate) gave 662 mg of the title A compound.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[C:4]([F:19])[CH:3]=1.[F:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])I>CS(C)=O.O.[Cu]>[F:19][C:4]1[CH:3]=[C:2]([C:22]([F:25])([F:24])[C:21]([F:27])([F:26])[F:20])[CH:18]=[CH:17][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[O:7]
Reactant: FC(F)(F)C(F)(F)I
Reactant: COc1cc(NC(=O)c2ccc(Br)cc2F)ccn1
Agent: [Cu]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2F)ccn1
Temperature: 120 °C
Yield: 22.3 %

Procedure:
To a stirred solution of 4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (800 mg, 2.46 mmol) and copper (1.6 g, 24.61 mmol) in DMSO (15 mL), in a bomb, 1,1,1,2,2-pentafluoro-2-iodo-ethane (4.1 g, 16.47 mmol) was bubbled through. The vessel was sealed and heated at 120° C. for 16 hours. The reaction mixture was diluted with water and filtered through a plug of silica and then extracted with ethyl acetate (4×). The organics combined, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to yield a crude mixture that was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-40%) to give 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (200 mg, 22%) as an off white solid. ESI-MS m/z calc. 364.06. found 365.3 (M+1)+; Retention time: 1.39 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.11 (d, J=6.3 Hz, 1H), 7.95 (dd, J=7.4 Hz, 1H), 7.89 (d, J=9.9 Hz, 1H), 7.72 (d, J=9.1 Hz, 1H), 7.23-7.19 (m, 2H), 3.85 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.Cl.[F:9][C:10]([F:15])([F:14])[CH2:11][CH2:12][NH2:13].C(N(CC)CC)C.[S-:23][C:24]#[N:25].[K+].II>C(#N)C>[C:2]([C:3]1[S:23][C:24](=[NH:25])[N:13]([CH2:12][CH2:11][C:10]([F:15])([F:14])[F:9])[CH:4]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)CC=O
Reactant: N#C[S-]
Reactant: NCCC(F)(F)F
Agent: Cl
Agent: II
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cn(CCC(F)(F)F)c(=N)s1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3,3-dimethylbutanal (0.64 g, 6.0 mmol), 3,3,3-trifluoropropan-1-amine hydrochloride (Oakwood) (0.9 g, 6.0 mmol), 2 g of 4 Å (8-12 mesh beads) molecular sieves, and triethylamine (0.84 mL, 6.0 mmol) in 9 mL of dry acetonitrile was stirred for 20 hours at ambient temperature. The mixture was filtered through Celite and washed with 8 mL of acetonitrile. Potassium thiocyanate (0.78 g, 8.0 mmol) was added and the mixture warmed to 50° C. Iodine (1.5 g, 6.0 mmol) was added and the reaction stirred at 50° C. for 6 hours. To the mixture 10 mL of 20% Na2S2O5 was added, and stirring continued for 30 minutes. The organic layer was separated, dried with Na2SO4, filtered, and the solvent removed under reduced pressure. The resulting solid was used without further purification. 1H NMR (500 MHz, ACETONITRILE-D3) δ ppm 1.30 (s, 9H), 2.72-2.84 (m, 2H), 4.28 (t, J=6.87 Hz, 2H), 6.92 (s, 1H). MS (DCI/NH3) m/z 253.0 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][O:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:16]1)=O)(C)(C)C>ClCCl>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[O:22][CH2:21][CH:17]1[CH2:18][CH2:19][CH2:20][NH:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCCC(COc2nc3ccccc3s2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2sc(OCC3CCCNC3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
Trifluoroacetic acid (2 mL) was added to 1-tert-butoxycarbonyl-3-[(benzothiazol-2-yl)oxymethyl]piperidine (460 mg, 1.32 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 3 hours. Subsequently, the solvent was evaporated and water was added to the residue, followed by a 1 mol/L aqueous sodium hydroxide solution to make the mixture basic. The mixture was then extracted with ethyl acetate and the extract washed with brine. The washed product was dried over magnesium sulfate and the solvent was evaporated to give 297 mg (91%) of the desired compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].[CH2:14]=O.C[O-].[Na+].Cl>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[CH2:14]
Reactant: COC(=O)Cc1ccc(Cl)cc1Cl
Reactant: C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: C=C(C(=O)OC)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichlorophenylacetic acid methyl ester (4.62 mmol) in 9 mL DMSO were added paraformaldehyde (4.85 mmol) and NaOMe (0.23 mmol). The reaction mixture was stirred at RT for 1 h and then poured into ice cold water. The mixture was neutralized with 1M HCl solution and extracted with toluol (3×). The combined organic layers were washed with aq. NaCl solution, dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (9/1 to 8/2) gives the desired compound as colorless oil;
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=3)[C:38]([O:40][CH3:41])=[O:39])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:45][CH2:46]OS(C)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:52]=[N+:53]=[N-:54].[Na+].CN(C=O)C>O>[N:52]([CH2:46][CH2:45][C:15]1[N:14]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:22]2[C:17]([C:16]=1[CH2:24][CH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]3[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=3)[C:38]([O:40][CH3:41])=[O:39])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)=[N+:53]=[N-:54]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cccc(-c2ccc(S(=O)(=O)CCc3c(CCOS(C)(=O)=O)n(C(c4ccccc4)c4ccccc4)c4ccc(Cl)cc34)cc2)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccc(S(=O)(=O)CCc3c(CCN=[N+]=[N-])n(C(c4ccccc4)c4ccccc4)c4ccc(Cl)cc34)cc2)c1
Temperature: 60 °C
Yield: 99 %

Procedure:
Methyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)benzoate (1 eq), sodium azide (5 eq), and DMF (0.05M) were placed together under N2 and heated to 60° C. After 1 hour the reaction was cooled and water was added. Extracted with EtOAc/Et2O mix and washed with water and brine and dried over sodium sulfate. Removed solvent to obtain methyl 3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (light-yellow solid) in 99% yield.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.O>N1C=CC=CC=1>[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cn[nH]c1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cccn2)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 15.3 %

Procedure:
A suspension of pyrazole (1 g) and 4-toluenesulfonyl chloride (2.8 g) in pyridine (10 ml) was stirred at 130° C. for 1 hour. After the reaction mixture was cooled, water was added to the reaction mixture, resulting in a white suspension. The resultant suspension was filtered, and the obtained white solids were washed three times with water. Drying at room temperature under reduced pressure gave white solids (500 mg).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[N:7]([CH2:10][CH2:11][CH3:12])=[N+:8]=[N-:9].O[C@H:14]([C@@H]1C([O-])=C(O)C(=O)O1)CO.[Na+].O>S([O-])([O-])(=O)=O.[Cu+2].C(O)CCC>[CH2:10]([N:7]1[CH:14]=[C:6]([CH2:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[N:9]=[N:8]1)[CH2:11][CH3:12]
Reactant: C#C[Si](C)(C)C
Reactant: CCCN=[N+]=[N-]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: CCCn1cc(C[Si](C)(C)C)nn1
Reaction time: 96 h

Procedure:
Trimethylsilylacetylene, 1-azidopropane, copper (II) sulfate and sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate were added to a 1:2 solution of water:butan-1-ol. The reaction was stirred for 4 days and t-butanol and water were removed, producing a 1-propyl-4-((trimethylsilyl)methyl)-1H-1,2,3-triazole solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.[C:29]([Si:33](Cl)([CH3:35])[CH3:34])([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([Si:33]([O:5][C:4]([O:6][CH3:7])=[C:3]([O:2][CH3:1])[CH3:8])([CH3:35])[CH3:34])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)C(C)OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(C)=C(OC)O[Si](C)(C)C(C)(C)C
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of methyl 2-methoxypropionate (177 mg, 1.5 mmol) in THF (1 mL) was added to a solution of LDA prepared from diisopropylamine (0.212 mL, 1.50 mmol) and butyllithium (0.60 mL, 1.50 mmol) in THF (2 mL) at −78° C. under nitrogen. The mixture was gradually allowed to warm to −20° C. over 1 h, re-cooled to −78° C. and then a solution of tert-butylchlorodimethylsilane (233 mg, 1.50 mmol) in THF (1 mL) was added. The mixture was allowed to warm to rt over 2 h and stirred overnight. The reaction was quenched with satd. NaHCO3 (5 mL), diluted with DCM (10 mL). The organic layer was separated, washed with water, brine and dried (MgSO4). Evaporation of solvents afforded tert-butyl((1,2-dimethoxyprop-1-en-1-yl)oxy)dimethylsilane as a clear oil and used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[NH2:7][C:8]1[C:13]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19](NC(=O)C)=[CH:18][CH:17]=2)=[CH:12][C:11]([N+:26]([O-:28])=[O:27])=[CH:10][N:9]=1.O1CCCC1.C[N:35](C)C=O>>[N+:26]([C:11]1[CH:12]=[C:13]2[CH:14]=[C:15]([C:16]3[CH:17]=[C:18]([NH:35][C:2](=[O:4])[CH3:1])[CH:19]=[CH:20][CH:21]=3)[NH:7][C:8]2=[N:9][CH:10]=1)([O-:28])=[O:27]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)Nc1ccc(C#Cc2cc([N+](=O)[O-])cnc2N)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(-c2cc3cc([N+](=O)[O-])cnc3[nH]2)c1
Temperature: 70 °C
Yield: 68 %

Procedure:
Potassium tert-butoxide (2.25 g, 20 mmol) was added to a solution of N-[4-(2-amino-5-nitro-pyridin-3-ylethynyl)-phenyl]-acetamide (1.48 g, 5 mmol) in a 2:1 mixture of tetrahydrofuran and dimethylformamide (75 mL). The mixture was heated at 70° C. for 16 hours then the tetrahydrofuran was removed in vacuo. The mixture was poured onto a pad of silica and eluted with 10% methanol in ethyl acetate. The organics were concentrated in vacuo to 5% of their original volume and water (30 mL) was added. The resultant orange solid was filtered and dried to afford N-[3-(5-Nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-acetamide (1.01 g, 68%).
Reaction SMILES: [C-:1]#[N:2].[K+].[NH4+:4].[Cl-].[CH2:6]1[C@H:19]2[C@@H:10]([CH2:11][C:12]3[C:17]([CH2:18]2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][CH2:8][C:7]1=O>CO.O.C(Cl)Cl>[NH2:4][C:7]1([C:1]#[N:2])[CH2:8][CH2:9][C@H:10]2[C@@H:19]([CH2:18][C:17]3[C:12]([CH2:11]2)=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:6]1
Reactant: [C-]#N
Reactant: [NH4+]
Reactant: O=C1CC[C@@H]2Cc3ccccc3C[C@H]2C1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: N#CC1(N)CC[C@@H]2Cc3ccccc3C[C@H]2C1

Procedure:
410 mg of KCN (6.3 mmol) and 340 mg of NH4Cl (6.3 mmol) are added, in succession, to a solution, stirred vigorously and maintained under nitrogen, containing 1.25 g (6.2 mmol) of the compound obtained in Step 4 in 30 ml of MeOH and 15 ml of water. After stirring for 12 hours at 20° C., the solution is diluted in CH2Cl2 and extracted with CH2Cl2. The organic phase is washed with a saturated NaCl solution, dried over MgSO4 and evaporated. The residue is treated with 25 ml of a methanolic solution of ammonia (7N) and stirred in a closed system for 12 hours at 20° C. Evaporation under reduced pressure yields the title compound in pure form.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.CCCCCC.CCOC(C)=O>[CH2:12]([O:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)nc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To a stirred mixture of 6-chloro-3-nitropyridin-2-ol (5 g, 0.0286 mol, Combi Blocks) in toluene (50.0 mL) in a 250 mL sealed tube, were added Ag2CO3 (11.84 g, 0.041 mol, Aldrich) and benzyl bromide (5.8 g, 0.033 mol) in one lot. The reaction mixture was capped, and the mixture was stirred for 12 h at 110° C. temperature. After completion of the reaction (monitored by TLC, 10% EtOAc in hexane), the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brown solid which was further purified column chromatography, silica gel (60-120 mesh) using 2-6% EtOAc in petroleum ether as an eluent to obtain the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ: 8.30 (d, J=8.1 Hz, 1H), 7.54 (d, J=6.9 Hz, 2H), 7.42-7.26 (m, 3H), 7.09 (t, J=8.4 Hz, 1H), 5.58 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:40])=[C:4]([S:9]([N:12]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.[O:50]([C:57]1[CH:65]=[CH:64][CH:63]=[CH:62][C:58]=1[C:59]([OH:61])=O)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.CCN=C=NCCCN(C)C>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([OH:40])=[C:4]([S:9]([N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[CH2:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:59](=[O:61])[C:58]2[CH:62]=[CH:63][CH:64]=[CH:65][C:57]=2[O:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:31][CH:32]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Reactant: CC(C)CNCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(Cc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)C(=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.5 %

Procedure:
3,5-Dichloro-N-((4′-fluorobiphenyl-4-yl)methyl)-2-hydroxy-N-(3-((isobutyl amino)methyl)benzyl)benzene sulfonamide (0.04 g, 0.066 mmol, 1 eq) was dissolved in acetonitrile. DIPEA (0.034 mL, 0.198 mmol, 3 eq) was added to the solution followed by 2-phenoxy benzoic acid (0.014 g, 0.066 mmol, 1 eq), EDCI (0.018 g, 0.099 mmol, 1.5 eq) and HOIST (0.013 g, 0.099 mmol, 1.5 eq). The reaction mixture was stirred at ambient temperature for 12 h and concentrated to remove all the volatiles. The residue obtained was dissolved in ethyl acetate and the organic layer was washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound (0.025 g, 50%). 1H NMR (400 MHz, DMSO-d6) δ 0.64-0.65 (d, 3H), 0.74-0.78 (t, 3H), 1.74 (s, 1H), 1.9 (t, 1H), 3.6 (t, 1H), 3.8 (t, 1H), 4.2 (m, 2H), 4.41-4.45 (m, 4H), 6.86-6.93 (m, 3H), 6.92-6.99 (m, 3H), 7.00-7.13 (m, 7H), 7.14-7.26 (m, 3H), 7.28-7.39 (m, 5H), 7.44-7.47 (d, 1H), 7.54-7.61 (m, 3H), 7.73-7.74 (d, 1H), 7.83-7.84 (d, 1H). MS (ESI): 798.7 (M+H)+.
Reaction SMILES: [CH2:1]1[C:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl>[O:19]1[C@@:10]23[C@H:5]([CH2:4][CH2:3][O:2][CH2:1]2)[CH2:6][CH2:7][CH2:8][CH:9]13
Reactant: C1=C2COCCC2CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C1CC2O[C@@]23COCC[C@@H]3C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3,4,4a,5,6,7-hexahydro-1H-isochromene (0.410 g, 2.97 mmol) in CH2Cl2 (10 mL) at 0° C. was added MCPBA (˜77%, 1.24 g, 445 mmol). The mixture was stirred at rt for 3 hr. It was quenched with sat'd aq. sodium sulfite. The mixture was diluted with CH2Cl2 and sat'd. aq. NaHCO3 then extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 4.03-4.10 (m, 1H), 3.86 (d, 1H, J=12.0 Hz), 3.54-3.62 (m, 1H), 3.34 (d, 1H, J=12.0 Hz), 3.03 (d, 1H, J=4.4 Hz), 1.70-1.98 (m, 3H), 1.52-1.65 (m, 3H), 1.17-1.34 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N([CH2:21][CH3:22])CC)C.C(=O)(O)[O-:24].[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:21](=[O:24])[CH3:22])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C([O-])O
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(4-Nitrophenyl)piperazine (2.5 g, 12.1 mmol) was dissolved in dichloromethane (100 ml). Triethylamine (2.0 ml, 14.5 mmol) was added and the reaction was cooled to 0° C. Atetic anhydride (1.25 ml, 13.3 mmol) was added dropwise and the reaction was stirred at 0° C. for 1 h. Saturated sodium bicarbonate was added and the reaction was extracted (×3) with dichloromethane, dried (MgSO4), filtered and concentrated in vacuo to give 4-(4-nitrophenyl)-1-acetylpiperazine as a yellow solid (3.01 g). GC/MS (EI, M+) m/z=249.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([C:30]#[N:31])([CH2:24]OS(C)(=O)=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([C:30]#[N:31])([CH2:24][O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(COS(C)(=O)=O)CC1
Reactant: Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1OCC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 117.4 %

Procedure:
After dissolving 230 mg of 2-methylphenol in 20 ml of N,N-dimethylformamide, 43 mg of sodium hydride (70% suspension in oil) was added and the mixture was stirred at 80° C. for 30 minutes. Next, 224 mg of 1-(tert-butoxycarbonyl)-4-cyano-4-(methanesulfonyloxymethyl)piperidine was added and the mixture was stirred at 100° C. for 8 hours. After cooling it to room temperature, water was added and extraction was performed with ethyl acetate. The organic layer was washed with a 1N sodium hydroxide solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (273 mg, 100% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:59]=[CH:58][C:7]([O:8][C:9]2[CH:10]=[C:11]([N:15]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]4[CH:54]=[CH:53][C:52]([N+:55]([O-])=O)=[CH:51][CH:50]=4)[CH:43]=3)[C:16]3[CH:28]=[CH:27][C:26]4[C:25]5[C:20](=[CH:21][C:22]([C:29]6[S:30][C:31]7[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=7[N:33]=6)=[CH:23][CH:24]=5)[C:19]([CH2:40][CH3:41])([CH2:38][CH3:39])[C:18]=4[CH:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.O1CCCC1.C(O)C.O.NN>[Pd].O>[NH2:1][C:4]1[CH:59]=[CH:58][C:7]([O:8][C:9]2[CH:10]=[C:11]([N:15]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]4[CH:50]=[CH:51][C:52]([NH2:55])=[CH:53][CH:54]=4)[CH:43]=3)[C:16]3[CH:28]=[CH:27][C:26]4[C:25]5[C:20](=[CH:21][C:22]([C:29]6[S:30][C:31]7[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=7[N:33]=6)=[CH:23][CH:24]=5)[C:19]([CH2:38][CH3:39])([CH2:40][CH3:41])[C:18]=4[CH:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CCC1(CC)c2cc(-c3nc4ccccc4s3)ccc2-c2ccc(N(c3cccc(Oc4ccc([N+](=O)[O-])cc4)c3)c3cccc(Oc4ccc([N+](=O)[O-])cc4)c3)cc21
Agent: [Pd]
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCC1(CC)c2cc(-c3nc4ccccc4s3)ccc2-c2ccc(N(c3cccc(Oc4ccc(N)cc4)c3)c3cccc(Oc4ccc(N)cc4)c3)cc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of N,N-di[3-(4-nitrophenoxy)phenyl]-7-(benzothiazol-2-yl)-9,9-diethyl-fluoren-2-amine (Example 7; 13.68 g, 17.2 mmol) in 300 mL of 1/1 tetrahydrofuran/ethanol mixture under argon was added 10% palladium/carbon (500 mg). The mixture was heated to 60° C., and hydrazine hydrate (12.7 mL, ˜206 mmol) was added slowly over 40 min by addition funnel. The solution became dark, fluorescent green and, after 8 hr, was cooled to room temperature and poured into 1.5 L of distilled water. After a few hours of stirring to evaporate some THF, a fine yellow solid was filtered and purified by column chromatography eluting with ethyl acetate/toluene. The product was further slurried in 100 mL of hot EtOH, filtered at room temperature, and dried in vacuo at 70° C. overnight to give 8.4 g (65%). 1H NMR (400 MHz, CDCl3) δ ppm: 8.08 (m, 2H), 8.01 (dd, J1=8 Hz, J2=1.6 Hz, 1H), 7.91 (d, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.48-7.55 (m, 1H), 7.35-7.42 (m, 1H), 7.05-7.18 (m, 4H), 6.52-6.59 (m, 2H), 3.5-3.6 (br. s, 4H), 1.95-2.15 (m, 4H), 0.34 (t, J=7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ ppm: 168.97, 159.73, 154.38, 152.23, 150.91, 149.04, 148.61, 147.69, 144.56, 142.72, 135.98, 135.07, 131.71, 129.98, 127.39, 126.42, 125.11, 124.19, 123.08, 121.68, 121.59, 121.19, 121.00, 119.60, 119.54, 117.90, 116.31, 113.33, 111.70, 56.57, 32.77, 8.73; MS (m/z): 736 (M+); Anal. Calcd. for C48H40N4O2S: C, 78.23%; H, 5.47%; N, 7.60%; S, 4.35%%. Found: C, 78.01%%; H, 5.60%%; N, 7.62%%; S, 4.31%.