Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]1[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:11][CH:12]1[CH2:14][CH2:13]1
Reactant: Oc1cc(F)ccc1Br
Reactant: BrCC1CC1
Product: Fc1ccc(Br)c(OCC2CC2)c1

Procedure:
Starting from commercially available 2-bromo-5-fluoro-phenol and commercially available bromomethyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×103 mbar.
Reaction SMILES: [CH2:1]([C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:47]1[CH2:51][CH2:50][CH:49]([C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)[CH2:48]1>CN(C=O)C>[CH2:1]([C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:47]1[CH2:51][CH2:50][CH:49]([C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)[CH2:48]1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1cncc(C2CCNC2)c1
Reactant: O=C(O)c1cnoc1Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnoc1Cc1ccccc1)N1CCC(c2cccnc2)C1
Reaction time: 2 h
Yield: 18 %

Procedure:
A solution of 5-benzylisoxazole-4-carboxylic acid (10 mg, 0.05 mmol), TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.10 mmol, 2 equ) in DMF (0.3 mL) was added to 3-pyrrolidin-3-yl-pyridine (7 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (3 mg). MS (ESI, pos. ion) m/z calcd for C20H19N3O2: 333.1477, found 333.1477.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH:9]3[CH2:11][CH:10]3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH2:18][O:19][CH:20]2[CH2:26][CH:25]3[N:27]([C:28]4[S:29][C:30]5[CH:36]=[C:35]([C:37]([O:39]CC)=[O:38])[CH:34]=[CH:33][C:31]=5[N:32]=4)[CH:22]([CH2:23][CH2:24]3)[CH2:21]2)[CH2:3][CH2:2]1.CO.O.[Li+].[OH-]>C1COCC1>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH:9]3[CH2:11][CH:10]3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH2:18][O:19][CH:20]2[CH2:26][CH:25]3[N:27]([C:28]4[S:29][C:30]5[CH:36]=[C:35]([C:37]([OH:39])=[O:38])[CH:34]=[CH:33][C:31]=5[N:32]=4)[CH:22]([CH2:23][CH2:24]3)[CH2:21]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc2nc(N3C4CCC3CC(OCc3c(C5CC5c5ccccc5)noc3C3CC3)C4)sc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2nc(N3C4CCC3CC(OCc3c(C5CC5c5ccccc5)noc3C3CC3)C4)sc2c1

Procedure:
A suspension of ethyl 2-(3-((5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylate (0.03 g, 0.05 mmol) in THF:MeOH:H2O=3:2:1 solution (0.6 mL) was treated with 6N LiOH (0.05 mL) at rt for 14 h. The volatiles were removed in vacuo, the residue diluted with water (1 mL), and 6N HCl was added to adjust pH to 2. The solids were collected by filtration and dried under vacuum to afford 2-(3-((5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6 carboxylic acid as hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7]([C:9](Cl)(Cl)Cl)=[N:8][C:4]=2[CH:3]=1.[CH:15]([NH:18][CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].C([O-])(O)=[O:23].[Na+]>C1COCC1.O>[CH:15]([N:18]([CH:19]([CH3:21])[CH3:20])[C:9]([C:7]1[NH:6][C:5]2[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1)=[O:23])([CH3:17])[CH3:16]
Reactant: O=C([O-])O
Reactant: Clc1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Reactant: CC(C)NC(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C(=O)c1nc2cc(Cl)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 500.0 mg (1.85 mmol) 5-Chloro-2-trichloromethyl-1H-benzoimidazole in 20 mL THF was added slowly to a mixture of 286 μl (2.04 mmol) diisopropyl-amine and 1.55 g (18.5 mmol, 10 equivalents) NaHCO3 in 70 mL THF and 20 mL water. The reaction mixture was stirred for 2 h at RT. The organic solvent was evaporated. The formed crystalline material was filtered off and treated once with about 50 mL of a saturated NaHCO3-solution under ultrasonic conditions. The crystalline residue was filtered off again and washed twice with 20 mL water. Drying under reduced pressure at 35° C. gave pure 5-Chloro-1H-benzoimidazole-2-carboxylic acid diisopropylamide in form of a light brown crystalline solid.
Reaction SMILES: [BH4-].[Na+].II.[Cl:5][C:6]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:7]=1[C:8](O)=[O:9].CC(=O)OCC>C1COCC1>[Cl:5][C:6]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:7]=1[CH2:8][OH:9]
Reactant: O=C(O)c1cc(I)ccc1Cl
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cc(I)ccc1Cl
Temperature: 0 °C

Procedure:
A 250 mL of 4-necked flask equipped with thermometer and mechanical stirring was charged with NaBH4 (4.16 g, 0.11 mol) and THF (60 mL) under argon. After cooling to 0˜5° C. with stirring, a solution of iodine in THF (12.7 g I2 in 25 mL THF) was added slowly dropwise over 30 min and the reaction temperature was maintained below 10° C. After the addition was completed, a solution of 2-chloro-5-iodobenzoic acid (15.0 g, 50 mmol) in THF (20 mL) was added dropwise over 30 min and kept the reaction temperature below 10° C. After stirring for another 3 h at 20˜25° C., the reaction mixture was heated to reflux for additional 16 h and monitored by TLC (PE/EA=1:1, Rf=0.2). The mixture was cooled to 20˜25° C. and poured into ice water (100 mL), extracted with ethyl acetate (2×100 mL), washed with water (2×100 mL), brine (100 mL), concentrated and the residue was purified by flash chromatography (PE:EA=20:1 as eluant, 200 mL) to give an off-white solid. Yield: 10.0 g (70%) MS ESI (m/z): 269 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH3:32]>CN(C)C=O>[CH2:30]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[CH2:31][CH3:32]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(O)c2)cc1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cccc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 9.5 h

Procedure:
To a solution of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)carbamate (0.300 g) in N,N-dimethylformamide (2.5 mL) was added potassium carbonate (0.194 g). Then 1-bromopropane (0.119 mL) was added, and the resulting mixture was stirred at room temperature for 9.5 hours. Potassium carbonate (0.180 g) and 1-bromopropane (0.110 mL) were added, and stirring was continued at room temperature for additional 14 hours. The reaction mixture was partitioned between diethyl ether (30 mL) and water (10 mL). The organic layer was washed successively with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.333 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])OC(C)(C)C)[CH2:3][CH2:2]1.Cl[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:33](=[O:36])([O-])[O-].[K+].[K+]>CN(C)C=O>[C:21]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19]/[CH:18]=[CH:17]\[CH2:16][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:36][C:33]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:5][CH2:6]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: ClC/C=C\CC(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CCN(C/C=C\CC(c2ccccc2)c2ccccc2)CC1)c1ccccc1Oc1ccccc1
Temperature: 60 °C
Yield: 133.9 %

Procedure:
A stirred suspension of 1.16 g (5.78 mmol) of 4-piperidinylcarbamic acid, 1,1-dimethylethyl ester (Example 1 Part B), 1.35 g (5.26 mmol) of (Z)-1-chloro-5,5-diphenyl-2-pentene, and 799 mg (5.78 mmol) of potassium carbonate in 15 mL of N,N-dimethylformamide was heated to 60° C. for eighteen hours, cooled, filtered and concentrated to a dark oil which was chromatographed on silica gel (150 g) eluted with 95:5 methylene chloride/methanol to provide 1.82 g (82%) of title compound, as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Cl[S:21]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)[S:21]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)(=[O:23])=[O:22])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-27 from bis(4-methoxybenzyl)amine and methyl 4-(chlorosulfonyl)-benzoate (Example 5-10c). MS (M−H, 440.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.68 (s, 6H), 4.20 (s, 4H), 6.77 (d, 4H, J=10 Hz), 6.98 (d, 4H, J=10 Hz), 7.92 (dd, 2H J=8 Hz), 8.06(dd, 2H, J=8 Hz). Elemental analysis: (found): C, 62.45%, H, 5.19% and N, 3.06%; (theoretical): C, 62.57%, H, 5.25% and N, 3.17%
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:16][CH2:17][C:18]1[C:19](=[O:32])[NH:20][C:21]([CH3:31])=[CH:22][C:23]=1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([C:23]1[CH:22]=[C:21]([CH3:31])[NH:20][C:19](=[O:32])[C:18]=1[CH2:17][NH:16][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=2[N:9]=[CH:10][CH:11]=1)=[O:15])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)n1ncc2c(C(=O)O)ccnc21
Reactant: Cc1cc(Cc2ccccc2)c(CN)c(=O)[nH]1
Product: Cc1cc(Cc2ccccc2)c(CNC(=O)c2ccnc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for example 11 from 1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.060 g, 0.292 mmol) and 3(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1H)-pyridinone (0.081 g, 0.307 mmol) wherein the product obtained was further purified by reverse phase HPLC (Gradient B: 5-85%. A:Dichloromethane. B: 10% (2M Ammonia in Methanol) in Chloroform). The isolated product was concentrated from MTBE (2×) to afford a white solid (93 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, J=6.57 Hz, 6 H), 2.10 (s, 3 H), 3.98 (s, 2 H), 4.45 (d, J=5.05 Hz, 2 H), 5.24 (quin, J=6.63 Hz, 1 H), 5.81 (s, 1 H), 7.12-7.30 (m, 5 H), 7.50 (d, J=4.55 Hz, 1 H), 8.33 (s, 1 H), 8.61 (d, J=4.55 Hz, 1 H), 8.88 (t, J=5.05 Hz, 1 H), 11.63 (s, 1 H). LCMS(ES) [M+H]+ 416.0
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13].[N:14]1([CH2:20][C:21]2[O:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[BH4-].[Na+]>C(O)C>[N:14]1([CH2:20][C:21]2[O:27][C:24]([CH2:25][NH:1][CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[NH:6][C:5]3=[O:13])=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NCCn1c(=O)[nH]c2ccccc21
Reactant: O=Cc1ccc(CN2CCCCC2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c2ccccc2n1CCNCc1ccc(CN2CCCCC2)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.4 %

Procedure:
In 100 ml of dry ethanol were dissolved 1.2 g (6.78 mmol) of Compound j and 1.3 g (6.78 mmol) of 5-piperidinomethylfurfural and the solution was stirred at room temperature for 20 hours. The reaction mixture was then cooled with ice and 1.18 g (31.1 mmol) of sodium borohydride was gradually added. The mixture was further stirred under ice-cooling for 1.5 hours. The reaction mixture was then concentrated, and after addition of methylene chloride, the resulting solution was washed with 2 portions of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. Finally the residue was purified by silica gel column chromatography (chloroform-methanol=10:1→chloroform-methanol-triethylamine=100:10:1) to give 1.26 g (52.9%) of Compound 18 as light yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.O1CCCC1.C([Li])CCC.[Br:18][C:19]1[S:20][CH:21]=[C:22]([Br:24])[N:23]=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[Br:18][C:19]1[S:20][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:22]([Br:24])[N:23]=1
Reactant: CCOC(=O)Cl
Reactant: Brc1csc(Br)n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(Br)nc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
In a 50 mL 2-neck RBF equipped with septa, a solution of N,N-Diisopropylamine (0.04374 g, 0.4322 mmol) in tetrahydrofuran (1.33 mL, 16.4 mmol) under atmosphere of argon was cooled at −78° C., at which point n-butyllithium (2.50 M in hexane, 0.1647 mL, 0.4116 mmol) was added dropwise and the resulting solution was stirred for 30 minutes at −78° C. To the above solution was added dropwise a solution of 2,4-dibromothiazole (0.100 g, 0.412 mmol) in tetrahydrofuran (1.33 mL, 16.4 mmol) at −78° C., and this solution was stirred for 30 min −78° C. Next, ethyl chloroformate (0.07872 mL, 0.8233 mmol) was added dropwise at −78° C. and the mixture was stirred for 30 minutes. The reaction was quenched by addition of water (20 mL), the layers were separated, and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (12 g Analogix column, gradient elution 5% to 10% EtOAc in hexane) to afford ethyl 2,4-dibromo-1,3-thiazole-5-carboxylate (60 mg, yield 46%). LC/MS: (FA) ES+ 314, 316, 318; 1H NMR (400 MHz, CDCl3) δ 4.37 (q, J=7.1, 2H), 1.44-1.33 (m, 3H).
Reaction SMILES: O[CH:2]([C:4]1[CH:21]=[CH:20][C:7]2/[C:8](=[CH:17]/[C:18]#[N:19])/[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)[CH3:3].B(Br)(Br)Br.[CH2:26]([C:29]1[NH:30][C:31]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1)[CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH2:26]([C:29]1[N:33]([CH:2]([C:4]2[CH:21]=[CH:20][C:7]3/[C:8](=[CH:17]/[C:18]#[N:19])/[C:9]4[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=4[CH2:11][CH2:12][C:6]=3[CH:5]=2)[CH3:3])[C:32]2[CH:34]=[CH:35][CH:36]=[C:37]([CH3:38])[C:31]=2[N:30]=1)[CH2:27][CH3:28]
Reactant: CCCc1nc2cccc(C)c2[nH]1
Reactant: CC(O)c1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCCc1nc2c(C)cccc2n1C(C)c1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reaction time: 0.33 h
Yield: 44.4 %

Procedure:
[step 1] (E)-[2-(1-Hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (67 mg, 0.24 mmol) obtained in Example 83, step 2 was dissolved in dichloromethane (1 mL), boron tribromide (1.0 mol/L dichloromethane solution; 0.73 mL, 0.73 mmol) was added at 0° C., and the mixture was stirred for 20 min. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in DMA (0.5 mL), 2-propyl-4-methylbenzimidazole (63 mg, 0.36 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added, and the mixture was stirred at 70° C. for 4 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50) to give (E)-{2-[1-(2-propyl-4-methylbenzimidazol-1-yl)ethyl]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (46 mg, 45%).
Reaction SMILES: O[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][C:13]([CH:18]([CH3:20])[CH3:19])([CH3:17])[C:14](=[O:16])[N:15]=2)=[N:9][CH:10]=1)([CH3:4])[CH3:3].S(=O)(=O)(O)O.[OH-].[NH4+]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][C:13]([CH:18]([CH3:20])[CH3:19])([CH3:17])[C:14](=[O:16])[N:15]=2)=[N:9][CH:10]=1)([CH3:4])=[CH2:3]
Reactant: CC(C)C1(C)NC(c2ccc(C(C)(C)O)cn2)=NC1=O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: C=C(C)c1ccc(C2=NC(=O)C(C)(C(C)C)N2)nc1
Temperature: 0 °C
Yield: 95.5 %

Procedure:
To 6.4 g of 2-[5-(1-hydroxy-1-methylethyl)-2-pyridyl]-5-isopropyl-5-methyl-2-imidazolin-4-one is added with stirring and cooling (ice) 30 ml concentrated sulfuric acid. The mixture is stirred at room temperature for a further 30 minutes, then poured onto 100 ml ice. The pH of this mixture is adjusted to 4 with concentrated ammonium hydroxide and extracted with 3×200 ml ether. The combined extracts were washed with saturated brine, dried and concentrated to give 5.71 g yellow solid. Recrystallized from ether-hexane gave analytically pure 2-(5-isopropenyl-2-pyridyl)-5-isopropenyl-5-methyl-2-imidazolin-4-one, mp 123°-125° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[OH:27].O>CN(C=O)C>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc3ccccc3c2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 2-naphthol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 mL), extracted with EtOAc (2×50 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(naphthalen-2-yloxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:8]([N+:18]([O-:20])=[O:19])=[C:9]3[CH2:17][O:16][CH2:15][CH2:14][C:10]3=[N+:11]([O-])[CH:12]=2)=[N:2]1.P(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:8]([N+:18]([O-:20])=[O:19])=[C:9]3[CH2:17][O:16][CH2:15][CH2:14][C:10]3=[N:11][CH:12]=2)=[N:2]1
Reactant: O=[N+]([O-])c1c(Nc2ccon2)c[n+]([O-])c2c1COCC2
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1c(Nc2ccon2)cnc2c1COCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of 473 mg of Compound 6 obtained in the above step (2) in 30 ml of methylene chloride is added a solution of 935 mg of phosphorus tribromide in 1 ml of methylene chloride under ice cooling. The reaction mixture is stirred for 2 hours, mixed with ice water and neutralized with aqueous potassium carbonate under ice cooling. The organic layer is separated, and the aqueous layer is extracted with methylene chloride. The organic layers are combined, washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue is recrystallized from methylene chloride-isopropanol to give 407 mg of the titled compound 7 as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[CH3:21][O:22][C:23](=[O:30])/[CH:24]=[CH:25]/[CH2:26][C:27](O)=[O:28].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>ClCCl>[CH3:21][O:22][C:23]([CH2:24][CH:25]=[CH:26][C:27]([N:9]([CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])=[O:28])=[O:30]
Reactant: COC(=O)/C=C/CC(=O)O
Reactant: O=C(CNCc1ccccc1Br)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC=CC(=O)N(CC(=O)OCc1ccccc1)Cc1ccccc1Br
Reaction time: 2 h

Procedure:
Benzyl 2-(N-(2-bromophenylmethyl)amino)acetate was dissolved in dichloromethane (0.2 M), followed by addition of trans-glutaconic acid methyl ester (1.2 eq), triethylamine (2 eq), EDAC (1.2 eq), and HOAT (0.1 eq). After stirring for 2 hrs, the solution was washed with 10% HCl, 10% sodium carbonate, water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50% EtOAc/Hex) afforded a viscous oil. EI-MS m/z 460, 462 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[C:9]2[O:10][CH2:11][CH:12]=[CH:13][CH2:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.CO.[H][H]>[Pd]>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:1])[C:9]1=2
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2c1OCC=CC2
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1OCCCC2
Reaction time: 8 h
Yield: 87 %

Procedure:
Into a Parr pressure reactor was placed 9-nitro-2,5-dihydro-benzo[b]oxepine (200 mg, 0.001 mol) in methanol (10 mL, 0.3 mol). To this solution was added palladium on carbon 10% (10 mg). The reaction was placed under 50 psi hydrogen and shaken overnight. Reaction mixture was filtered through celite, rinsed with methanol (3×10 mL) and concentrated in vacuo to give 2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine as an off-white solid (142 mg, 83%).