Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>ClCCl.C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:24]([C:21]1[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:28])[F:29])=[CH:23][CH:22]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(F)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=S(=O)(Nc1ccc(F)cc1F)c1ccc(C(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 34.6 %

Procedure:
To 2,4-difluoro-phenylamine (1, 2.09 mL, 20.7 mmol) in 13.04 mL of dichloromethane, pyridine (0.522 mL, 6.45 mmol) was added and the mixture was stirred under nitrogen for 20 minutes. 4-Trifluoromethyl-benzenesulfonyl chloride (2, 5.00 g, 20.4 mmol) was added slowly and the reaction was stirred overnight. The reaction mixture was treated with 2 mL of 1 M hydrochloric acid in diethyl ether and allowed to sit for 1 hour. The solid precipitate was filtered off, and the filtrate was extracted with 1 N aqueous hydrochloric acid followed by brine. The organic portion was dried over magnesium sulfate, filtered and the filtrate was concentrated under vacuum. The resulting solid was treated with dichloromethane, and the solid was collected and dried to provide the desired compound as a white solid (3, 2.383 g).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl>CCOC(C)=O.CO>[CH:20]1([C:18]([NH:17][CH2:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][NH2:8])=[CH:15][CH:14]=2)=[O:19])[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)C2CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NCc1ccc(CNC(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
Dissolve N-(tert-butoxycarbonyl)-4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamine (529 mg, 1.74 mmol) in EtOAc (20 mL) and MeOH (15 mL). Bubble hydrogen chloride through the solution for 15 min, and stir the mixture overnight at room temperature. Concentrate the mixture in vacuo and dissolve the resulting solid in water. Adjust the pH to 9-11 with 20% aqueous K2CO3 (w/w %) and extract three times with chloroform/iso-propanol (3:1). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (40 g, pre-packed cartridge) eluting with DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) (1:0 over 5 min, 19:1 over 5 min, 9:1 over 5 min, 4:1 over 5 min, 1:1 over 10 min, 1:3; 50 mL/min) to obtain the desired intermediate (275 mg, 77%). MS (APCI+) m/z: 188 (M-NH3+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13](=[O:15])[CH3:14])=[CH:8][C:7]=1[CH:16]([CH3:18])[CH3:17].[OH:19][C:20]1[C:21]([CH3:32])=[C:22]([C:25]([O:30][CH3:31])=[C:26]([CH3:29])[C:27]=1[CH3:28])[CH2:23]Cl.C(N(CC)CC)C>CN(C)C=O>[OH:19][C:20]1[C:21]([CH3:32])=[C:22]([C:25]([O:30][CH3:31])=[C:26]([CH3:29])[C:27]=1[CH3:28])[CH2:23][N:2]([CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13](=[O:15])[CH3:14])=[CH:8][C:7]=1[CH:16]([CH3:18])[CH3:17])[CH3:1]
Reactant: COc1c(C)c(C)c(O)c(C)c1CCl
Reactant: CNCCOc1cc(C)c(C(C)=O)cc1C(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1c(C)c(C)c(O)c(C)c1CN(C)CCOc1cc(C)c(C(C)=O)cc1C(C)C
Temperature: 25 °C
Yield: 95.1 %

Procedure:
N-Methyl-2-(4-acetyl-2-isopropyl-5-methylphenoxy)ethylamine (6.75 g) and 3-hydroxy-6-methoxy-2,4,5-trimethylbenzyl chloride (5.48 g) were dissolved in N,N-dimethylformamide (80 ml), and triethylamine (2.58 g) was added dropwise while stirring the mixture at room temperature. The mixture was stirred at room temperature for 16.5 hours. After the reaction, the solvent was distilled off, and water was added. The mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained liquid was purified by silica gel chromatography (eluent; ethyl acetate/benzene=1/1) to give 10.38 g of a pale-yellow solid. The obtained solid was recrystallized from isopropyl alcohol to give 7.22 g of the title compound (colorless crystals).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:21])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[CH3:10].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.[NH4+].[Cl-]>C1COCC1.CN1C(=O)N(C)CCC1>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][C:13]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]([O:11][CH2:9][CH3:10])=[O:21]
Reactant: CCOC(=O)C(C)c1ccccc1
Reactant: BrCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C(C)(CCCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of LDA (14 mL, 28 mmol, 2.0 M in heptane) was added dropwise to a stirred solution of 202 (5.0 g, 28.06 mmol) in anhydrous THF (50 mL) at −78° C. After 1 h, the reaction mixture was added to a −78° C. cold solution of 1,4-dibromobutane (10.06 g, 23.1 mmol) in THF. After the addition of DMPU (5 mL), the reaction mixture was stirred for 1 h, then warmed to room temperature and stirred overnight. The mixture was poured into saturated aqueous NH4Cl solution (500 mL) and extracted with ethyl acetate (4×100 mL). The combined organic phases were washed with brine (100 mL), 1 M HCl (50 mL), saturated aqueous NaHCO3 solution (50 mL), and brine (100 mL). The solution was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was distilled to give 205d as an oil (7.16 g, 99%). Bp 130-131° C./0.2 mm Hg. 1H NMR (CDCl3), δ (ppm): 7.40-7.15 (m, 5H), 4.13 (q, 2H, J=6.7), 3.36 (t, 2H, J=6.7), 2.02 (m, 2H), 1.86 (m, 2H), 1.56 (s, 3H), 1.34 (m, 2H), 1.18 (t, 3H, J=6.7). 13C NMR (CDCl3), δ (ppm): 176.13, 143.91, 128.51, 126.81, 126.03, 60.93, 50.22, 38.53, 33.56, 33.30, 23.58, 22.77, 14.22. HRMS (FAB): Calcd for C15H2179BrO2 (MH+): 313.0803, found 313.0786.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH:14]([C:18]([O:20][CH3:21])=[O:19])[CH2:13]2)=[N:4][N:3]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>[C:22]([N:15]1[CH2:16][CH2:17][N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([Cl:1])=[N:3][N:4]=2)[CH2:13][CH:14]1[C:18]([O:20][CH3:21])=[O:19])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C1CN(c2nnc(Cl)c3ccccc23)CCN1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 4-(4-chlorophthalazin-1-yl)piperazine-2-carboxylate (563 mg, 1.84 mmol) was dissolved in DMF (6 mL) and N,N-diisopropylethylamine (1 mL). Benzoyl chloride (0.23 mL, 2.02 mmol) was added and the mixture stirred at rt for 16 hours. The reaction was taken up in ethyl acetate (80 mL), washed with aqueous K2CO3 (10%), water, and then saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-75% ethyl acetate gave an off-white foam. MS (M+H)+=381.8.
Reaction SMILES: [I-].[Na+].Cl[CH2:4][C:5]([NH2:7])=[O:6].C1(C)C=CC=CC=1.[CH2:15]([O:22][C:23]([NH:25][CH:26]([C:32]([O:34]CC)=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]CC.[Na+]>C(O)C>[CH2:15]([O:22][C:23]([NH:25][C:26]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:4][C:5](=[O:6])[NH:7][C:32]1=[O:34])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC(=O)CCl
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Agent: CC[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(NC(=O)OCc2ccccc2)CC(=O)NC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To 123 kg of ethanol, 25.0 kg (167 mol) of sodium iodide and 14.2 kg (152 mol) of α-chloroacetamide were added and the resultant mixture was heated to 77° C. and was stirred for 3 hours. To the resultant suspension, 58.2 kg (130 mol) of 69% toluene solution of diethyl 2-benzyloxycarbonylaminomalonate was added, followed by cooling the resultant mixture to 0° C. Thereto, 89.1 kg (262 mol) of 20% ethanol solution of sodium ethoxide was dropped for 3 hours while maintaining the temperature at 0° C. After the reaction mixture was stirred for 3 hours at 0° C., the reaction was quenched by adding 7.9 kg of acetic acid and 15.1 kg of 85% phosphoric acid to the reaction mixture and the solvent was distilled off under reduced pressure. To the reaction mixture, 200 kg of toluene and 80 kg of water were added and the phase separation of the reaction mixture was performed. After the organic phase was washed with water 3 times, it was quantitatively analyzed and the yield of 2-benzyloxycarbonylamino-2-ethoxycarbonyl succinimide was found to be 87.5%. This solution was concentrated and then was recrystallized with toluene and ethanol to thereby obtaining 30 kg (yield: 72%) of 2-benzyloxycarbonylamino-2-ethoxycarbonyl succinimide as a white crystal.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C([O-])(O)=O.[Na+]>Cl.O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1cc(Cl)nc2ccccc12
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOc1cc(NCCCOc2cccc(CN3CCCCC3)c2)nc2ccccc12
Temperature: 160 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (9.93 g) and 2-chloro-4-ethoxyquinoline (4.15 g) were heated, with stirring, at 160° C. for 41/4 hours. The reaction mixture was cooled to give a glass which was dissolved in dilute HCl to give a solution having a pH of 6. This solution was washed with diethyl ether (2×), taken to pH 5 and extracted continuously into chloroform. The chloroform extract was evaporated under reduced pressure to give a residue which was dissolved in water, taken to pH 9 with aqueous NaHCO3, and extracted into diethylether (7×) and chloroform (2×). These extracts were dried (MgSO4) and evaporated to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-4-ethoxyquinoline as an oil (7.92 g). This was dissolved in hot ethanol and treated with maleic acid in ethanol to give the dimaleate salt (7.53 g), m.p. 145.5°-147.5° C. (recrystallised from ethanol).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Li])(CC)C.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=[O:24]>C(OCC)C>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]([CH:12]1[CH2:11][CH2:10][CH2:9][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[OH:24]
Reactant: O=Cc1ccco1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC1C(O)c1ccco1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
N-Boc-pyrrolidine (5.0 g) was dissolved in diethyl ether (60 mL) and the solution was cooled to −78° C. N,N,N′,N″-Tetramethylethylenediamine (TMEDA) (4.4 mL) was added to the mixture followed by sec-butyl lithium (27.0 mL, 1.3 M in cyclohexane) maintaining the temperature below −60° C. After 2 h, 2-furaldehyde (2.9 mL) was added and the mixture was stirred at −70° C. for an additional 30 min. The reaction mixture was allowed to warm to room temperature and was then quenched with water and poured into EtOAc (200 mL). The separated organic layer was washed with saturated aq. ammonium chloride (3×50 mL) followed by brine (50 mL), dried (MgSO4), and concentrated. The crude product was purified by column chromatography (heptane/EtOAc, 8/1; 5/1) to afford 4.97 g of 2-furyl(N-Boc-pyrrolidin-2-yl)methanol as a mixture of diastereomers. The resulting 2-furyl(N-Boc-pyrrolidin-2-yl)methanol (4.43 g) was dissolved in dichloromethane (200 mL) and trifluoroacetic acid (30 mL) was added. The mixture was poured into a 1 M solution of sodium hydroxide. The organic layer was separated and washed with saturated aq. sodium bicarbonate (2×100 mL). The aqueous layers were extracted with dichloromethane (4×50 mL) and the combined organic layers were concentrated. The crude product was purified by column chromatography (CH2Cl2/methanol/NH4OH, 95/5/1; 90/10/1). The resulting oil was distilled in a Kugelrohr apparatus (175-200° C., 0.2 Torr) to afford 0.20 g of the title compound as a mixture of diastereomers. Physical characteristics. MS (ESI+) m/z 168 (M+H)−.
Reaction SMILES: C([NH:9][C:10]([NH:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[CH2:15][CH2:14]1)=[O:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>>[O:23]=[C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]([NH:12][C:10]([NH2:9])=[O:11])[CH2:14][CH2:15]1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NC1CCC(=O)c2ccccc21
Yield: 72.7 %

Procedure:
A mixture of 1-benzoyl-3-(1,2,3,4-tetrahydro-4-oxo- 1-naphthyl)urea (3.8 g) and aqueous sodium hydroxide (2N; 38 ml) is stirred and heated at reflux for 70 minutes. The mixture is then cooled in ice and the product is collected and washed with water to afford 1.83 g of the title compound, m.p. 212° to 215° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH3:17]O>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:17])=[O:10]
Reactant: O=C(O)Cc1ccccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1O
Temperature: 90 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
2-Hydroxyphenylacetic acid (302.7 mg, 1.99 mmol) was dissolved in anhydrous methanol (10 mL), and sulfuric acid (0.2 mL) was added thereto, and then the reaction mixture was stirred at 90° C. for 6 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate (50 mL), 1N aqueous NaOH solution (5 mL), and saturated aqueous NaHCO3 solution (30 mL) were added to the reaction mixture and separated. The organic layer was washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the titled reference compound (242.4 mg) as a yellow solid. (Yield 73%)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([OH:11])=[C:4]([F:12])[CH:3]=1>[Pd].CO>[NH2:8][C:6]1[CH:7]=[CH:2][CH:3]=[C:4]([F:12])[C:5]=1[OH:11]
Reactant: O=[N+]([O-])c1cc(Br)cc(F)c1O
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(F)c1O

Procedure:
To a stirred slurry of 10% palladium on carbon (2.26 g, 2.12 mmol) in MeOH (100 mL) was added 4-bromo-2-fluoro-6-nitrophenol (5.00 g, 21.2 mmol). The reaction mixture was stirred under an H2 atmosphere until significant reduction was seen by TLC. The mixture was filtered through Celite and concentrated in vacuo. The resultant solid was triturated with hexanes and reconcentrated to remove residual MeOH and give 2-amino-6-fluorophenol as a dark gray solid. 1H NMR (DMSO-d6, 300 MHz) δ 10.86 (br s, 1H), 9.54 (br s, 2H), 7.25–7.19 (m, 1H), 7.13 (d, 1H), 6.94–6.86 (m, 1H).
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])[CH:33]([C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)[CH2:32][CH2:31]2>C1C=CC=CC=1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])=[C:33]([C:52]1[CH:53]=[CH:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=1)[CH:32]=[CH:31]2
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2CCCCCCCCCCCC(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2CCCCCCCCCCCC(=O)O)cc1

Procedure:
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0.31 g.) and p-toluenesulphonic acid (0.005 g.) were successively added to a stirred solution of 12-[(1RS, 2RS)-6-methoxy-2-p-methoxyphenyl-1,2,3,4-tetrahydronaphth-1-yl]dodecanoic acid (0.29 g.) in benzene (30 ml.), and the mixture was stirred and heated under reflux for 2 hours whilst a stream of argon was bubbled through it. The mixture was cooled and filtered, the filtrate was evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 2:1 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil 12-(6-methoxy-2-p-methoxyphenylnaphth-1-yl)dodecanoic acid, which was a starting material for compounds described in Table 1.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([F:58])[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([F:58])[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(F)cccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(F)cccc4c3=O)cc2)CCC1
Yield: 79.3 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(8-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (35 mg, 0.072 mmol) was reacted to give the title compound (22 mg, 79%). LCMS (Method F): RT=9.24 min, [M+H]+=386. 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J=8.6 Hz, 1H), 7.49-7.29 (m, 7H), 7.26 (d, J=8.1 Hz, 2H), 7.17 (d, J=8.1 Hz, 2H), 2.58-2.48 (m, 2H), 2.24-1.97 (m, 3H), 1.79-1.68 (m, 1H).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH:16]([C:18]([OH:20])=O)[S:17][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:13][CH:12]=[CH:11][CH:10]=4.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:18]([CH:16]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:17]1)=[O:20])[CH3:22]
Reactant: O=C(O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Reactant: CCNCC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)C(=O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
To 6,11-dihydro-5-thia-11-aza-benzo[α]fluorene-6-carboxylic acid (1.65 g, 6 mmol) in CH2Cl2 (15 ml) were added diethylamine (0.7 ml, 7 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (2.75 g, 6 mmol) and diisopropylethylamine (3.1 ml, 18 mmol). The reaction was stirred at room temperature for 3 days. The reaction mixture was diluted with CH2Cl2 (100 ml), washed with 1N HCl, saturated NaHCO3 soln, brine, dried (MgSO4) and evaporated. The residue was purified by silica gel chromatography eluting with 50% EtOAc/petroleum ether to give 1.07 g (54%) of 6,11-dihydro-5-thia-11-aza-benzo[α]fluorene-6-carboxylic acid diethylamide as a yellow solid. 1H NMR (CDCl3) δ 9.23 (1H, s), 7.33 (1H, dd), 7.20 (1H, dd), 7.69-7.08 (5H, m), 6.66-6.72 (1H, m), 5.33 (1H, s), 3.34-3.76 (4H, m), 1.39 (3H, t), 1.37 (3H, t).
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:17])=[CH:8][C@@H:9]2[C:14]([OH:16])=O)[CH:2]=[CH2:3].[CH3:18][O:19][C:20]1[CH:45]=[CH:44][C:23]([CH2:24][O:25][C:26]2[C:31]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[CH:30][N:29]=[C:28]([CH2:42][NH2:43])[CH:27]=2)=[CH:22][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:17])=[CH:8][C@H:9]2[C:14]([NH:43][CH2:42][C:28]1[CH:27]=[C:26]([O:25][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:45][CH:44]=2)[C:31]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)=[CH:30][N:29]=1)=[O:16])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@@H]2C(=O)O
Reactant: COc1ccc(COc2cnc(CN)cc2OCc2ccc(OC)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(=O)NCc1cc(OCc2ccc(OC)cc2)c(OCc2ccc(OC)cc2)cn1
Yield: 36.1 %

Procedure:
To a solution of (R)-6-(allyloxy)-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxylic acid (Intermediate 32, 0.469 g, 1.97 mmol) in DMF (10 mL) at room temperature was added (4,5-bis(4-methoxybenzyloxy)pyridin-2-yl)methanamine (Intermediate 65, 0.824 g, 2.17 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.497 g, 3.94 mmol) and N,N-diisopropylethylamine (1.372 mL, 7.87 mmol). After 30 minutes the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate, brine, and 1/1 brine/water twice. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-50% ethyl acetate/hexanes) afforded the title compound as a light pink foam (0.427 g, 36%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=O)[CH2:6][CH2:5]1)[CH3:3].O.[NH2:16][NH2:17]>C(O)C>[CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH:16][NH2:17])=[O:12])[CH2:6][CH2:5]1)[CH3:3]
Reactant: NN
Reactant: CCOC(=O)C1CCN(C(C)C)CC1
Solvent: CCO
Solvent: O
Product: CC(C)N1CCC(C(=O)NN)CC1
Temperature: 25 °C

Procedure:
3.60 g (18.1 mmol) of ethyl 1-(1-methylethyl)piperidin-4-carboxylate and 1.00 g (19.9 mmol) of hydrazine hydrate were initially charged in 15 ml of ethanol and stirred at reflux for 16 h. The reaction mixture was cooled to RT and concentrated, and the residue was lyophilized. The crude product was triturated with diethyl ether (25 ml), filtered off and dried. This gave 1.91 g (57% of theory) of the product.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]1([S:35]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](B(O)O)=[CH:39]2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:40]1[C:41]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]([S:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:37])=[O:36])[CH:39]=1)=[N:3][C:4]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)nc21

Procedure:
2-(1-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol was reacted with 1-(phenylsulfonyl)-1H-indol-3-ylboronic acid via General Procedure B to give intermediate 2-(1-((9-methyl-6-morpholino-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol. The intermediate was suspended in MeOH (3 mL) whereupon 3N KOH (0.3 mL) was added and the reaction mixture was heated at 50° C. for several hours until the protecting group was removed. Reverse phase purification gave 115. MS (Q1) 490.3 (M)+. 1H NMR (400 MHz, DMSO) δ 11.46 (s, 1H), 8.67-8.51 (m, 1H), 8.13 (d, 1H), 7.53-7.25 (m, 2H), 7.20-7.07 (m, 2H), 4.27 (s, 4H), 4.02 (s, 1H), 3.84 (s, 3H), 3.76 (dd, 12.2, 4H), 3.69 (s, 2H), 2.88 (d, 2H), 1.97 (t, 2H), 1.66 (d, 2H), 1.21 (dt, 3H), 1.02 (s, 6H)