Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH2:12][CH:13]3[N:18]([CH3:19])[CH:17]([C:6]2=1)[CH2:16][CH2:15][CH2:14]3.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1.C1(C=CC(O)=CC=1)O>CS(C)=O.O>[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:28][CH2:27][C:24]1[CH:23]=[N:22][C:21]([CH3:20])=[CH:26][CH:25]=1)[C:7]1[CH2:12][CH:13]3[N:18]([CH3:19])[CH:17]([C:6]2=1)[CH2:16][CH2:15][CH2:14]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1C
Reactant: C=Cc1ccc(C)nc1
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CC2CCCC1N2C
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A reaction flask with a septum cap was charged with 30% sodium metal dispersion in paraffin wax (0.30 g, 4.0 mmol; Aldrich) and a solution of 2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (0.48 g, 2.0 mmol; Example 114A) in dimethyl sulfoxide (4 mL). The vessel was sealed, flushed with nitrogen, and stirred for 10 minutes. A solution of 2-methyl-5-vinylpyridine (0.238 g, 2.0 mmol; prepared as described in International Publication No. WO 2001017968) and hydroquinone (0.072 g, 0.66 mmol; Aldrich) in anhydrous dimethyl sulfoxide (1.5 mL) was added and the reaction was heated at 100° C. for 72 hours. After cooling the mixture to room temperature, it was poured into water and extracted with ethyl acetate (4×25 mL). The combined organic extracts were washed with brine, concentrated, and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 15 minutes] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 0.82-1.00 (m, 1H), 1.17-1.30 (m, 1H), 1.32-1.42 (m, 1H), 1.55-1.64 (m, 1H), 1.78-1.99 (m, 3H), 2.15 (s, 3H), 2.40 (s, 6H), 2.66 (dd, J=17, 7 Hz, 1H), 3.06-3.15 (m, 3H), 4.03 (t, J=3 Hz, 1H), 4.30-4.37 (m, 2H), 6.95 (dd, J=8, 1 Hz, 1H), 7.08-7.14 (m, 2H), 7.26 (d, J=8 Hz, 1H), 7.32 (dd, J=8, 2 Hz, 1H), 7.82 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 360 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23].O=C1C2C(=CC=CC=2)C2C(CC(N)=O)=CC=CC=2N1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[O:20]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:24]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:22][CH3:23])[CH:19]=[CH:18][C:17]=2[NH:16]1
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: CCCNCCC
Agent: NC(=O)Cc1cccc2[nH]c(=O)c3ccccc3c12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN(CCC)CC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Prepared from the compound of Example 2 and dipropylamine. To a solution of 2-chloro-N-(5,6-dihydro-6-oxo-2-phenanthridinyl-acetamide (45 mg) in N,N-dimethylformamide (10 mL) was added potassium phosphate (68 mg) and dipropylamine (0.027 mL). The solution stirred at room temperature for 5 hours followed by evaporation of the solvent. The light brown product was washed with water and filtered (25 mg). 1H-NMR (300 MHz, DMSO-d6), 11.70 (br s, 1H), 9.72 (br s, 1H), 8.33 (d, J=8.0 Hz, 2H), 7.89 (m, 1), 7.66 (m, 2H), 7.33 (m, 1H), 3.21 (s, 2H), 1.50 (m, 6H), 0.89 (m, 8H).
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([OH:7])=[O:6].CN(C=O)C.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][CH2:21][OH:22]>C1COCC1>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][CH2:21][O:22][CH2:4][C:5]([OH:7])=[O:6]
Reactant: OCCOC1CCCCO1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)COCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a stirred suspension of NaH (60% dispersion in mineral oil, 4.80 g, 120 mmol) in THF, at 0° C., was added a THF solution (15 ml) of bromoacetic acid (6.11 g, 44 mmol). Mixture was stirred at room temperature 0.5 hr, then a DMF solution (15 ml) of alcohol 1 (5.84 g, 40 mmol) was added dropwise. Mixture was stirred at room temperature for 17 hrs then quenched with H2O and extracted twice with ether. Aqueous layer was acidified to pH 2-3 and extracted with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated to give pure compound 2 as a pale yellow oil (6.93 g, 85%) used for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:30][C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)[C:34]([O:36][CH3:37])=[O:35]>CS(C)=O.O>[CH3:1][C:2]1[N:6]([CH2:30][C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34]([O:36][CH3:37])=[O:35])[N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[N:8]=2)[N:3]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a solution of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (311 mg, 1.0 mmol) in DMSO (5 mL), Cs2CO3 (652 mg, 2.0 mmol) and methyl 3-(bromomethyl)benzoate (252 mg, 1.1 mmol) were added at RT. The mixture was stirred at RT for 2 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4×40 mL). The combined organic layers werewashed with H2O (20 mL) and brine (2×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by a silica gelchromatography (EtOAc/Hexane 10% to 60% EtOAc) to give methyl 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)benzoate as a white solid (310 mg, 68%). MS (ES+) C21H16F3N5O4 requires: 459. found: 460 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.29 (d, J=8.8 Hz, 2H), 8.04 (d, J=7.4 Hz, 1H), 7.95 (s, 1H), 7.48 (t, J=7.5 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.3 Hz, 2H), 5.51 (s, 2H), 3.92 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)=[O:6].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:28]1[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[C:30]([CH3:38])[C:29]=1[O:39][CH3:40])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CN(C)C=O>[CH3:40][O:39][C:29]1[C:30]([CH3:38])=[C:31]([CH3:37])[C:32]([O:35][CH3:36])=[C:33]([CH3:34])[C:28]=1[CH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: COc1c(C)c(C)c(OC)c(C(CCCCCCI)c2ccccc2)c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCCCCC(c2ccccc2)c2c(C)c(OC)c(C)c(C)c2OC)cc1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 98.1 %

Procedure:
A 0.42 g (10×1.05 mmole) quantity of sodium hydride (60%, oily preparation) was added to a solution of 1.52 g (10.0 mmole) of methyl p-hydroxybenzoate in dimethylformamide (15 ml) under ice-cooling, followed by stirring for 5 minutes. The cooling bath was removed, and a solution of 4.80 g (10.0 mmole) of 1-iodo-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-phenylheptane in dimethylformamide (15 ml) was added to the mixture. Then, the temperature was raised to 50° C., and stirring was effected for 1 hour. After ice-cooling, dilute hydrochloric acid was added to suspend the reaction, and the product was extracted with isopropyl ether. The isopropyl ether layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residual solution was chromatographed on a silica gel column to perform purification (elution with hexane/isopropyl ether) to thereby give 4.95 g (98%) of methyl 4-[7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-phenylheptoxy]benzoate. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 14.
Reaction SMILES: N[C@@H](C[S:6][CH2:7][CH:8]1[CH2:10][CH2:9]1)CO.CN1CCOCC1.FC(F)(F)C(OS(C(F)(F)F)(=O)=O)C1C=CC=CC=1.C1C(C[C@:41]([NH:46][CH:47]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:48]([F:51])([F:50])[F:49])([CH3:45])[CH:42](S)[OH:43])C1>C1COCC1>[CH2:9]1[CH:8]([CH2:7][S:6][C@:41]([NH:46][CH:47]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:48]([F:49])([F:50])[F:51])([CH3:45])[CH2:42][OH:43])[CH2:10]1
Reactant: N[C@H](CO)CSCC1CC1
Reactant: C[C@](CC1CC1)(NC(c1ccccc1)C(F)(F)F)C(O)S
Agent: O=S(=O)(OC(c1ccccc1)C(F)(F)F)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@@](CO)(NC(c1ccccc1)C(F)(F)F)SCC1CC1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2(R)-amino-3-cyclopropylmethylsulfanylpropan-1-ol (80.5 mg, 0.5 mmol) in anhydrous THF (3 mL) were added activated 4 Å molecular sieves (250 mg) and N-methylmorpholine (51 mg, 0.5 mmol). After stirring for 10 min, trifluoromethanesulfonic acid 2,2,2-trifluoro-1-phenylethyl ester (190.5 mg, 0.5 mmol) was added and the reaction was stirred at room temperature for 2 days. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography to afford the desired mixture of diastereomers of 2(R)-3-cyclopropylmethyl-sulfanyl-2-(2,2,2-trifluoro-1(RS)-phenylethylamino)propan-1-ol. LC-MS: 318.3(M-1), 320.8(M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20](Br)=[CH:21][N:22]=3)[N:19]=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:24])[N:7]([C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:32]4[C:27]([O:26][CH3:25])=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:21][N:22]=3)[N:19]=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ncccc1B(O)O
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ncccc1-c1cnc2ccc(N3CC[C@H](N(C)C(=O)OC(C)(C)C)C3)nn12
Temperature: 150 °C
Yield: 77.7 %

Procedure:
A mixture of [(S)-1-(3-bromo-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidin-3-yl]-methyl-carbamic acid tert butyl ester (83 mg, 0.21 mmol), 2-methoxypyridine-3-boronic acid (43 mg, 0.28 mmol), K2CO3 (87 mg, 0.63 mmol) and dichlorobis(triphenylphosphine)palladium(II) (7.4 mg, 0.011 mmol) in MeCN/water (3.2 ml/0.8 ml) was heated in a microwave at 150° C. for 15 min. The water layer was removed and the organic layer was diluted with MeCN and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (69.3 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50 (s, 9H) 2.11-2.29 (m, 2H) 2.84 (s, 3H) 3.40 (dd, J=10.48, 6.95 Hz, 1H) 3.46-3.53 (m, 1H) 3.67-3.74 (m, 2H) 4.08 (s, 3H) 4.94 (br. s., 1H) 6.61 (d, J=9.60 Hz, 1H) 7.03 (dd, J=7.58, 4.80 Hz, 1H) 7.77 (d, J=9.85 Hz, 1H) 8.12-8.18 (m, 2H) 8.86 (dd, J=7.58, 1.77 Hz, 1H). LRMS (ESI) m/z 425.3 [(M+H)]+, calc'd for C22H28N6O3: 424.51.
Reaction SMILES: [CH:1]1([C:4]2[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=[C:6]([CH:16]=O)[CH:5]=2)[CH2:3][CH2:2]1.[CH2:18]([NH:20][C:21](=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)[CH3:19]>>[CH:1]1([C:4]2[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=[C:6]([CH2:16][N:31]3[CH2:30][CH2:29][N:28]([C:25]4[CH:24]=[CH:23][C:22]([C:21]([NH:20][CH2:18][CH3:19])=[O:34])=[CH:27][CH:26]=4)[CH2:33][CH2:32]3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC1Oc2c(cc(C=O)cc2C2CC2)NC1=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cc4c(c(C5CC5)c3)OC(C)C(=O)N4)CC2)cc1

Procedure:
Using 346A and N-ethyl-4-(piperazin-1-yl)benzamide 283 in the general procedure for reductive aminations, the title compound was obtained as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.60-0.70 (m, 2H) 0.88-0.94 (m, 2H) 1.09 (t, J=7.07 Hz, 3H) 1.43 (d, J=6.57 Hz, 3H) 2.04-2.12 (m, 1H) 2.41-2.49 (m, 4H) 3.17-3.29 (m, 6H) 3.36 (s, 2H) 4.64 (q, J=6.82 Hz, 1H) 6.41 (d, J=1.52 Hz, 1H) 6.69 (d, J=1.77 Hz, 1H) 6.92 (m, J=9.09 Hz, 2H) 7.71 (m, J=8.84 Hz, 2H) 8.17 (t, J=5.56 Hz, 1H) 10.55 (s, 1H). ESI-MS: m/z 449.4 (M+H)+.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[C:1]([N:5]([C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([Cl:27])=[C:18]([Cl:17])[CH:19]=1)[NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)NNC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccn1)C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 23 °C
Reaction time: 4 h
Yield: 79.1 %

Procedure:
A solution of N'-t-butyl-N-(2-pyridinecarbonyl)-hydrazine (0.5 g) in 10 ml of toluene was treated with 50% sodium hydroxide (0.61 g). 3,4-dichlorobenzoyl chloride (0.6 g) was added and the mixture was stirred rapidly for 4 hours at 23° C. and then was allowed to stand for 48 hours. The solids were removed by filtration and washed with water to afford 0.75 g of N'-t-butyl-N-(2-pyridinecarbonyl)-N'-(3,4-dichlorobenzoyl)hydrazine as a white solid. m.p. 175-178° C.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:31]1([CH2:37][CH2:38]Br)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:38][CH2:37][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: BrCCC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(CCC2CCCCC2)c1=O
Reaction time: 8 h
Yield: 42.7 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (1.0 g, 7.24 mmoles) and 2-cyclohexylethyl bromide (287 mg, 1.5 mmoles) in dimethylacetamide (8 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from toluene gave the title compound (180 mg, 42%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.15 (br. s., J=5.43, 5.43 Hz, 1 H), 4.63 (t, J=11.62 Hz, 1 H), 4.07-4.19 (m, 2 H), 3.72-3.88 (m, 2 H), 2.18-2.36 (m, 2 H), 1.50-1.87 (m, 10 H), 1.35-1.47 (m, 2 H), 1.04-1.35 (m, 7 H), 0.91 (q, J=11.62 Hz, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[H][H]>CO.[Pt]=O>[CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)CC(NCc1ccccc1[N+](=O)[O-])C(=O)OC
Agent: O=[Pt]
Solvent: CO
Product: COC(=O)CC(NCc1ccccc1N)C(=O)OC

Procedure:
A mixture of 2-(2-nitrobenzylamino)succinic acid dimethyl ester [from a) above] (7.6 g, 25.65 mmol) and platinum oxide (349.51 mg, 1.54 mmol) was shaken in methanol on a Parr hydrogenation apparatus under 50 psi of hydrogen gas. After 12 h the mixture was filtered and concentrated to give 6.6 g of the title compound as a light brown oil.
Reaction SMILES: [CH3:1][C@:2]12[C:9]3[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=3[N:7]([CH3:15])[C@H:6]1[N:5]([CH3:16])[CH2:4][CH2:3]2.C([Li])CCC.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C(COC)OC>[CH3:1][C@:2]12[C:9]3[CH:10]=[C:11]([O:14][C:29]([NH:28][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:30])[CH:12]=[CH:13][C:8]=3[N:7]([CH3:15])[C@H:6]1[N:5]([CH3:16])[CH2:4][CH2:3]2
Reactant: O=C=Nc1ccccc1
Reactant: CN1CC[C@@]2(C)c3cc(O)ccc3N(C)[C@@H]12
Agent: [Li]CCCC
Solvent: O
Solvent: COCCOC
Product: CN1CC[C@@]2(C)c3cc(OC(=O)Nc4ccccc4)ccc3N(C)[C@@H]12
Reaction time: 0.17 h
Yield: 96456.5 %

Procedure:
Eseroline base (50 g, 0.229 mol) was dissolved in 400 mL anhydrous dimethoxyethane under an argon atmosphere. Catalytic amounts of 2.5 M n-butyl lithium in hexanes (6.4 mL, 16 mmol) were added within 1 minute and the solution stirred for 10 minutes. Phenyl isocyanate (27.269 g, 0.2286 mmol) was added over 32 minutes keeping the temperature between 20 and 23° C. The reaction solution was stirred at r.t. for 2 hours 20 minutes, then transferred to an addition funnel. The reaction solution was added over 49 minutes to mixture of DI water (630 mL) and dimethoxyethane (42 mL) under vigorous stirring. The obtained slurry was stirred for 30 minutes, then filtered via a Buchner funnel (Whatman #3 filterpaper). The solid residue was washed four times with DI water (100 mL each) and once with heptane (100 mL), then dried at 45° C. and >29 inches of vacuum for 9 hours. Phenserine base (74.4 g) was obtained as reddish solid in 96.2% yield and 95.1% purity.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:6]=[CH:5]2.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C)C>[N:15]1([CH2:14][CH2:13][O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([C:26]2[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=2)[C:20]#[N:21])[CH:11]=[CH:10]3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1ccc2cc(OCCN3CCCC3)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: N#Cc1cccc(-c2ccc3cc(OCCN4CCCC4)ccc3c2)c1
Temperature: 85 °C

Procedure:
A mixture of the product from Example 37B (35 mg, 0.11 mmol), 3-cyanophenylboronic acid (22 mg, 0.15 mmol), PdCl2(PPh3)2 (4.2 mg, 6 μmol), and isopropanol (0.5 mL) was treated with 2 M aqueous sodium carbonate (80 μL) and heated at 85° C. overnight. The mixture was cooled to room temperature and partitioned between 2 M aqueous NaOH and dichloromethane. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were filtered through diatomaceous earth, concentrated, and chromatographed through silica with a gradient of 0%/50%/50% to 10%/40%/50% methanol/ethyl acetate/dichloromethane followed by 8% methanol/dichloromethane to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.86 (m, 4H), 2.73 (m, 4H), 3.01 (t, 2H), 4.28 (t, 2H), 7.22 (dd, 1H), 7.31 (d, 1H), 7.65 (t, 1H), 7.70 (dt, 1H), 7.75 (dd, 1H), 7.85-7.92 (m, 2H), 8.06 (dt, 1H), 8.07-8.13 (m, 2H); MS (ESI) m/z 343 (M+H)+.
Reaction SMILES: [CH2:1]([N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][CH:12]=[N:11][C:10]1=2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C(=O)N([Br:26])C(=O)C1>O1CCOCC1>[Br:26][C:17]1[N:9]([CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[N:11]=[CH:12][NH:13][C:14](=[O:18])[C:15]=2[N:16]=1
Reactant: O=c1[nH]cnc2c1ncn2CCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Product: O=c1[nH]cnc2c1nc(Br)n2CCc1ccccc1
Temperature: 105 °C
Yield: 57 %

Procedure:
To a solution of purinone from step 2 (0.29 g, 1.21 mmol) from above reaction in dioxane (0.1M) is added NBS (0.32 g, 1.81 mmol). The resulting reaction mixture was heated to 105° C. until HPLC shows consumption of starting material (ca. 2 h). The reaction was cooled to rt and purified by MPLC using a solvent gradient of 0-20% MeOH/CH2Cl2. The product containing fractions were collected and concentrated to provide the desired product (0.22 g, 57% yield). 1H NMR (DMSO-d6) δ 12.49 (s, 1H), 8.08 (s, 1H), 7.30-7.21 (m, 3H), 7.10-7.04 (m, 2H), 4.36 (t, J=7.0 Hz, 2H), 3.17 (t, J=7.3 Hz, 2H).
Reaction SMILES: C([Li])CCC.C(NC1CCCCC1)(C)C.[CH2:16]([C:18](=[C:21]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)C=O)[CH3:17].[O:36]1C[CH2:39][CH2:38][CH2:37]1>>[CH2:16]([C:18](=[C:21]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[CH:39]=[CH:38][CH:37]=[O:36])[CH3:17]
Reactant: C1CCOC1
Reactant: CCC(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Product: CCC(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Butyl lithium (25.7 mL of 2.1M solution, 54 mmol) was added to a solution of N-isopropylcyclohexylamine in 30 mL tetrahydrofuran at -10° C. After stirring for 30 minutes and cooling to -40° C., N-ethylidenecyclohexamine (27 mL of 2M solution, 54 mmol) was added and the solution stirred for 30 minutes. The solution was further cooled to -70° C. and 2-ethyl-3,3-bis(4-fluorophenyl)- 2-propenal(4.9 g, 18 mmol) in 40 mL of tetrahydrofuran was added. The mixture was stirred for 5 hours and quenched with water. The mixture was extracted with diethyl ether, the extracts dried over magnesium sulfate and concentrated in vacuo. The residue was stirred with a mixture of 100 mL of benzene, 40 mL of water and 60 mL of acetic acid for 16 hours and diluted with 1.50 mL of water. The organic layer was separated, washed with saturated sodium bicarbonate solution, dried with magnesium sulfate and concentrated in vacuo. The residue was crystallized from petroleum ether to give 3.45 g of the title compound; m.p. =98°-99.5° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOCC>[N:12]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: O=C1CCc2cc(F)ccc21
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=C1CCc2cc(-n3cccn3)ccc21
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Combine 5-fluoro-indan-1-one (1.02 g, 6.79 mmol), pyrazole (0.46 g, 6.79 mmol), and potassium carbonate (1.03 g, 7.47 mmol, 1.10 equivalents) in dimethyl sulfoxide (5 ml) in a sealed tube and heat to 100° C. for 48 hours. Cool to room temperature, dilute with ether, wash with water (2×), dry over anhydrous sodium sulfate, and concentrate to obtain the title compound as a brown solid (0.98 g, 73%). LC-MS m/z 199.1 (M++1).