Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[Li]CCCC.[F:13][C:14]([F:42])([F:41])[O:15][C:16]1[CH:17]=[C:18]([C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=2)=[N:23][S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH:19]=[CH:20][CH:21]=1>CCOCC>[CH3:29][C:26]([S:24]([NH:23][C:22]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:38])[F:39])[CH:31]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:13])([F:42])[F:41])[CH:17]=1)[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:25])([CH3:27])[CH3:28]
Reactant: CC(C)(C)[S@@](=O)N=C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: Cc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)S(=O)NC(Cc1ccccn1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
2-Picoline (0.20 mL, 2.0 mmol) was stirred in anhydrous Et2O (20 mL) at 0° C. under Argon. nBuLi (2.5 M in hexanes, 0.84 mL, mmol) was added dropwise. The reaction mixture turned to dark brown, and stirred at 0° C. for 20 min, then at room temperature for 1 h. It was cooled back to 0° C., and (R)—N-(bis(3-(trifluoromethoxy)phenyl)-methylene)-2-methylpropane-2-sulfinamide (prepared as described in Example 82, Procedure 11) (0.906 g, 2.0 mmol) in Et2O (4.0 mL) was added dropwise. The mixture was stirred at 0° C. for 1 h. then at room temperature for 1 h. The reaction was quenched by addition of sat'd NH4Cl. EtOAc was added; the organic layer was washed with H2O and brine, dried (Na2SO4), filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, EtOAc/Hexanes=0 to 100%) to give 2-methyl-N-(2-(pyridin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)-ethyl)propane-2-sulfinamide as light tan solids (0.19 g with recovery of 0.59 g of starting material, yield: 48% based on recovery of the starting material). LC-MS (ESI) 547.38 (M+H), retention time=3.90 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run); 1H NMR (400 MHz, CDCl3) δ ppm 8.36-8.44 (m, 1H), 7.90 (m, 1H), 7.51 (d, J=8.59 Hz, 1H), 7.37 (td, J=7.83, 2.27 Hz, 2H), 7.19-7.24 (m, 2H), 7.11-7.17 (m, 3H), 6.98-7.07 (m, 2H), 6.75 (d, J=7.83 Hz, 1H), 4.15 (d, J=13.90 Hz, 1H), 3.81 (d, J=13.90 Hz, 1H), 1.25-1.33 (m, 9H)
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=[C:10]([C:20]2[C:21]([O:26]CC3C=CC=CC=3)=[N:22][CH:23]=[CH:24][CH:25]=2)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:2]=[CH2:3]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:9][O:8][C:6](=[O:7])[C:5]1[C:10]([C:20]2[C:21](=[O:26])[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:11][C:12]([C:16]([CH3:17])([CH3:18])[CH3:19])=[C:13]([O:14][CH3:15])[C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: C=CCc1c(OC)c(C(C)(C)C)cc(-c2cccnc2OCc2ccccc2)c1C(=O)OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCc1c(OC)c(C(C)(C)C)cc(-c2ccc[nH]c2=O)c1C(=O)OC
Reaction time: 0.5 h

Procedure:
step 7—A mixture of 128 (17 mg) and Pd(OH)2/C (20 mg) in EtOAc (10 mL) was stirred under 1 atm H2 for 30 min then the catalyst was filtered off. The filtrate was concentrated to afford 4.9 mg of I-90 as a waxy solid.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.Cl.[CH3:13][CH:14]([CH3:34])[CH2:15][C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[NH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:17][C@@H:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:15][CH:14]([CH3:34])[CH3:13])=[N:3][CH:4]=1
Reactant: CC(C)C[C@@H](N)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1ccc(F)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N[C@H](CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 110 °C
Reaction time: 15 h
Yield: 107.4 %

Procedure:
A 1.0 L round bottom flask was charged with methyl 6-fluoronicotinate (14.2 g, 91.6 mmol), (R)-3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine hydrochloride (30.0 g, 87.3 mmol), potassium carbonate (36.2 g, 262 mmol) and N,N-dimethylformamide (300 mL). The reaction was heated to 110° C. and stirred for 15 hours. The reaction was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate and saturated ammonium chloride. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organic layers were washed with water (5×) and brine (1×), dried over sodium sulfate, filtered and concentrated to provide (R)-methyl-6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinate (41.5 g) as a light brown solid. 1H NMR (400 MHz, CDCl3, δ): 0.98 (d, J=6.24 Hz, 3H) 1.02 (d, J=6.24 Hz, 3H) 1.67-1.92 (m, 3H) 3.86 (s, 3H) 4.68-4.84 (m, 1H) 6.36 (d, J=8.97 Hz, 1H) 6.65 (br. s., 1H) 7.42-7.47 (m, 2H) 7.55-7.59 (m, 2H) 7.66-7.69 (m, 4H) 8.00 (dd, J=8.97, 2.15 Hz, 1H) 8.66 (d, J=1.95 Hz, 1H). MS (M+1): 443.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:17])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12](OCC)=[O:13])[CH:8]=[CH:7]2.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([F:17])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12][OH:13])[CH:8]=[CH:7]2
Reactant: CCOC(=O)c1ccc2cc(F)cc(Br)c2n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCc1ccc2cc(F)cc(Br)c2n1
Temperature: -78 °C

Procedure:
Ethyl 8-bromo-6-fluoroquinoline-2-carboxylate (3.201 g, 10.7 mmol) was weighed into a flask, and dissolved in 100 mL of DCM. The reaction was cooled to −78° C., followed by drop-wise addition of DIBAL-H (21.48 mL, 32.22 mmol) over 10 minutes. The reaction was then allowed to stir and warm to ambient temperature over 2 hours at which time the starting material had been consumed. The reaction was quenched with 10 mL MeOH, followed by addition of 100 mL of Rochelle's Salts, and stirred overnight to remove the emulsion. The reaction was then partitioned with ethyl acetate. The combined organic fractions were concentrated in vacuo. The crude semi solid was purified by flash column chromatography (eluting with a 20-50% ethyl acetate/hexanes gradient), affording the desired product as an orange-yellow semi solid (2.27 g, 42% yield) MS APCI (+) m/z 256.1 and 258 (M+1 of each Br isotope) detected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[CH:5]=[CH:6][CH2:7]Cl.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1>C(Cl)(Cl)Cl>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:7][CH:6]=[CH:5][C:4]3[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=3[O:2][CH3:1])[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: COc1ccccc1C=CCCl
Solvent: ClC(Cl)Cl
Product: COc1ccccc1C=CCN1CCc2nc(N)sc2CC1
Yield: 13 %

Procedure:
Prepared from 2-methoxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 13% of theory, Melting point: 80°-84° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[CH:22][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[O:31][C:32]=3[CH3:33])=[CH:22][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of ethyl 1-benzyl-3-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylate (1.50 g) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (0.22 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added sodium sulfate decahydrate (1.86 g) and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give {1-benzyl-3-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazol-4-yl}methanol as a colorless oil (1.13 g, yield 81%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][O:11][C@@H:12]([CH:17]=[CH2:18])[C:13]([F:16])([F:15])[F:14].Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[N:21][OH:22])[CH2:10][O:11][C@@H:12]([CH:17]=[CH2:18])[C:13]([F:16])([F:15])[F:14]
Reactant: NO
Reactant: C=C[C@H](OCC(=O)c1cccc(F)c1F)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=C[C@H](OCC(=NO)c1cccc(F)c1F)C(F)(F)F
Temperature: 50 °C

Procedure:
(S)-1-(2,3-difluorophenyl)-2-((1,1,1-trifluorobut-3-en-2-yl)oxy)ethanone (3.91 g) was dissolved in anhydrous methanol (40 mL) and hydroxylamine hydrochloride (1.25 g) and sodium acetate (1.68 g) were added. The reaction mixture was heated to 50° C. for 90 min, then cooled to RT, concentrated in vacuo and the residue purified by silica gel chromatography (2% to 20% EtOAc in hexanes) to afford the title compound as a mixture of geometric isomers (4.10 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 4.04-4.26 (m 1H), 4.43-4.55 (m, 0.4H) 4.80-4.89 (m, 1.6H) 5.39-5.55 (m, 2H) 5.64-5.80 (m, 1H) 7.05-7.30 (m, 3H), 7.76 (br s, 0.2H), 8.30 (br s, 0.8H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.Br[CH:14]([CH2:16][CH3:17])[CH3:15]>CC#N>[CH:14]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)([CH2:16][CH3:17])[CH3:15]
Reactant: CCC(C)Br
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Solvent: CC#N
Product: CCC(C)c1c[nH]c2cc(N)ccc12

Procedure:
3-sec-Butyl-1H-indol-6-ylamine (B-14) was synthesized following the general scheme above starting from 6-nitroindole and 2-bromobutane. Overall yield (20%). HPLC ret. time 2.32 min, 10-99% CH3CN, 5 min run; ESI-MS 189.5 m/z (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([O:35][C:36](=[O:50])[NH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][C@H:47]([NH2:49])[CH3:48])[CH:41]=1)([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:31]([O:35][C:36](=[O:50])[NH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][C@H:47]([NH:49][CH2:21][C@@H:20]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16](=[O:19])[NH:17]3)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:48])[CH:41]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: C[C@@H](N)Cc1cccc(CCNC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](Cc1cccc(CCNC(=O)OC(C)(C)C)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 63.5 %

Procedure:
A stirred solution of 8-benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethyl-silanyloxy)ethyl]-1H-quinolin-2-one (3.14 g, 6.43 mmol); {2-[3-((R)-2-aminopropyl)phenyl]ethyl}carbamic acid tert-butyl ester (1.79 g, 6.43 mmol) and triethylamine (1.08 mL, 7.72 mmol) in DMF (21.0 mL) was microwaved (300 watts) at 80° C. for 15 h. Saturated aqueous sodium bicarbonate (10 mL) was added and the resulting mixture was extracted with DCM (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to give the title compound (2.8 g, 63% yield) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[S:13](Cl)(=[O:15])=[O:14].[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[S:13]([NH:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:15])=[O:14]
Reactant: COC(=O)c1sccc1N
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1Cl
Yield: 30.4 %

Procedure:
Synthesized as described for 3 using 2-chloro-4-(trifluoromethoxy)benzene-1-sulfonyl chloride (5.0 g; 16.94 mmol), methyl 3-aminothiophene-2-carboxylate (2.93 g; 18.63 mmol), 4-dimethylaminopyridine (517.0 mg; 4.23 mmol) pyridine (38.0 mL; excess) and anhydrous dichloromethane (100 mL). The resulting crude white crystalline solid was washed with acetone to afford the title compound as a white solid (2.14 g).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl:8][C:9]1(Cl)[CH2:11][C:10]1([CH3:13])[CH3:12].Cl>>[Cl:8][C:9]1[CH2:11][CH:2]2[C:1]([O:6][C:4](=[O:5])[CH:3]2[CH2:12][C:10]=1[CH3:13])=[O:7]
Reactant: CC1(C)CC1(Cl)Cl
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Product: CC1=C(Cl)CC2C(=O)OC(=O)C2C1
Yield: 13.6 %

Procedure:
To a glass tube was added maleic anhydride (73.3 mg., 0.75 mmole) and 1,1-dichloro-2,2-dimethylcyclopropane (119.3 mg., 0.86 mmole). The tube was sealed and heated at 165°-170°C. for 6-8 hours. The tube was allowed to cool and was opened (caution HCl pressure). The initially liquid product mixture crystallized with vigorous evolution of hydrogen chloride. Extraction of the crude solid (m.p. 60°-70°C.) with boiling n-hexane gave 1-chloro-2-methylcyclohexene-4,5-dicarboxylic anhydride (20.5 mg., 10 percent yield, white plates m.p. 76°-78°C.). The melting point of 1-chloro-2-methylcyclohexene-4,5-dicarboxylic anhydride as reported in the literature, J. Applied Chem. (London) 3, 145 (1953), is 79°-80°C.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:24][C:23]2[CH:25]=[C:26]([O:32][CH3:33])[C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:22]=2[NH:21][C:20](=[O:34])[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.I[CH2:36][CH3:37]>CCCCCC>[CH2:8]([O:15][C:16]([N:18]1[CH2:24][C:23]2[CH:25]=[C:26]([O:32][CH3:33])[C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:22]=2[N:21]([CH2:36][CH3:37])[C:20](=[O:34])[CH2:19]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCI
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(C(=O)OCc1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCN1C(=O)CN(C(=O)OCc2ccccc2)Cc2cc(OC)c([N+](=O)[O-])cc21
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of Sodium hydride (0.135 g, 0.00338 mol) and N,N-Dimethylformamide (40 mL, 0.5 mol) was added at 5° C. 7-Methoxy-8-nitro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid benzyl ester (1.00 g, 0.00269 mol) and stirred for 1 hour at room temperature. Iodoethane (0.286 mL, 0.00358 mol) was added and stirred for 3 hours. The solvent was evaporated and the residue taken up in water and ethyl acetate, separated, washed, dried and evaporated to a give a gum. Trituration with hexane gave 1-Ethyl-7-methoxy-8-nitro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-carboxylic acid benzyl ester as a red solid (1.01 g). (94%). Mp 55-56° C. LCMS (m/e) 400 (M+1); 1H-NMR (DMSO, 400 MHz) δ 8.02 (s, 1H), 7.58 (s, 1H), 7.50-7.30, (br, 5H), 5.15 (s, 2H), 4.56-4.48 (br, 2H), 3.94 (s, 3H), 3.91-3.84 (m, 4H), 1.05-1.01 (t, 3H, J=7.07 Hz).
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[C:11]([N+:12]([O-])=O)=[C:10]([CH3:15])[N:9]=[C:8]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:7]=1>O1CCCC1.[Zn]>[CH3:15][C:10]1[C:11]([NH2:12])=[C:6]([CH3:5])[CH:7]=[C:8]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[N:9]=1
Reactant: Cc1cc(N2CCOCC2)nc(C)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(N2CCOCC2)nc(C)c1N
Temperature: 0 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
Glacial acetic acid (25 mL) was added slowly to a mixture of zinc dust (2.76 g) and 4-(4,6-dimethyl-5-nitro-pyridin-2-yl)-morpholine (2.01 g) in tetrahydrofuran (100 mL) cooled to 0° C. The reaction mixture was then stirred for 16 hours at 25° C., filtered through celite, made basic with 25% aqueous ammonia and extracted with tetrahydrofuran (3×75 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to furnish 1.76 g (100%) of the title compound as a dark red solid. GC-MS (m/z) 207 (M+); tR=7.27. 1H NMR (500 MHz, DMSO-d6): 2.07 (s, 3H), 2.20 (s, 3H), 3.16 (m, 4H), 3.67 (m, 4H), 4.10 (b, 2H), 6.38 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]([OH:19])=O)=[C:6]2[C:10]=1[O:9][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N:7]2.Cl.Cl.[NH2:22][CH:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[CH:23]([NH:22][C:17]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:10]3[O:9][C:8]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[N:7][C:6]=13)=[O:19])[CH2:24]2
Reactant: O=C(O)c1ccc(Br)c2oc(-c3ccccc3)nc12
Reactant: NC1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC1CN2CCC1CC2)c1ccc(Br)c2oc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.9 %

Procedure:
A mixture of 7-bromo-2-phenylbenzo[d]oxazole-4-carboxylic acid (200 mg, 0.62 mmol), (±)-3-aminoquinuclidine dihydrochloride (148 mg, 0.74 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (237 mg, 1.24 mmol) and 1-hydroxybenzotriazole (167 mg, 1.24 mmol) in DMF (2.5 mL) was stirred 5 min at room temperature, then triethylamine (0.34 mL, 2.48 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) followed by semi-preparative HPLC to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-7-bromo-2-phenylbenzoxazole-4-carboxamide (34 mg, 13%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.41 (d, J=7.0 Hz, 1H), 8.29-8.26 (m, 2H), 8.09 (d, J=8.5 Hz, 1H), 7.66-7.57 (m, 4H), 4.31-4.27 (m, 1H), 3.51 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.15-2.85 (m, 4H), 2.81 (dd, J=14.0, 4.0 Hz, 1H), 2.17-2.14 (m, 1H), 2.07-2.02 (m, 1H), 1.79-1.61 (m, 3H); MS (ESI+) m/z 426 (M+H); HPLC>99% (AUC), tR=13.09 min.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][C@H:7]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:5]([OH:6])[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36]>O1CCCC1.O>[CH3:25][C:24]([Si:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:10][CH2:9][C@H:7]1[O:8][C@H:3]([CH2:2][NH:1][C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)=[O:36])[CH2:4][C@@H:5]1[OH:6])([CH3:27])[CH3:26]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@H](CN)C[C@@H]1O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CNC(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@@H]1O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
A slurry of 3.15 g of product from Example 283 and 1.35 g of potassium carbonate in 15 ml of tetrahydrofuran at 0° C., under argon, is treated with 2.11 g of p-nitrobenzyl chloroformate and the reaction is stirred vigorously at 0° C. for 4 hours. The reaction mixture is diluted with 100 ml of water, extracted with 3×100 ml of ethyl acetate, dried, concentrated in vacuo and purified by chromatography (Silica Gel: 5-50% ethyl acetate/hexane) to give 3.49 g of the desired product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](Cl)=[O:13])[CH2:8][CH2:7]1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:12]([CH:9]2[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]2)=[O:13])=[CH:18][CH:17]=1
Reactant: CN1CCC(C(=O)Cl)CC1
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Yield: 85 %

Procedure:
To a cold suspension of anhydrous aluminum chloride (20 g, 75 mmol) in chlorobenzene 30 ml at 0° C. was added 1-methylpiperidine-4-carboxylic acid chloride in small portions and the resulted mixture was refluxed for 3 hours. The reaction mixture was cooled down, poured into ice water. The organic phase was discarded. The aqueous solution was washed with 2×50 ml ethyl ether, basified with potassium hydroxide pellet slowly to pH>10 and extracted with ethyl ether 4×50 ml. The combined organic solution was dried over sodium sulfate and concentrated to give 11.2 g of desired product in 85% yield.
Reaction SMILES: O[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1[OH:11]>C(O)(=O)C.[C].[Pd]>[CH:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:2][C:3]2[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=2[OH:11])=[CH:13][CH:14]=1)([CH3:20])[CH3:19]
Reactant: Cc1cc(C)c(C(O)c2ccc(C(C)C)cc2)c(O)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(O)c1
Temperature: 90 °C
Yield: 90 %

Procedure:
A mixture of 2-(hydroxy(4-isopropylphenyl)methyl)-3,5-dimethylphenol obtained in Reference Example 147 (12.3 g, 45.5 mmol) and 10%-palladium carbon (50% hydrous, 1.23 g) in acetic acid (90 mL) was heated under hydrogen atmosphere at 90° C. for 16 hours. The catalyst was removed, and the reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed with 1 N aqueous sodium hydroxide solution and a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to obtain 10.5 g (yield 90%) of the title compound. Oily matter.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:11][N:10](C(OCC3C=CC=CC=3)=O)[CH2:9]2)[CH2:4][CH2:3]1>CO.[Pd]>[NH:10]1[CH2:11][CH:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH2:9]1
Reactant: CN1CCN(C2CN(C(=O)OCc3ccccc3)C2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C2CNC2)CC1
Yield: 100.2 %

Procedure:
A mixture of benzyl 3-(4-methylpiperazin-1-yl)azetidine-1-carboxylate (1.45 g, 5.01 mmol) and Pd/C (0.320 g, 0.150 mmol) in methanol (30 mL) was hydrogenated at 30 psi over the weekend. The reaction mixture was filtered through celite and the filtrate was concentrated. The crude product 1-(azetidin-3-yl)-4-methylpiperazine (0.78 g, 5.02 mmol, 100% yield) was obtained as colorless oil and used without purification.