Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][O:29][CH2:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccncc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCOCc4ccncc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 4-bromomethyl-pyridine.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:17][C:16]([Br:27])=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:20]([O:19][C:18]1[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=[C:16]([Br:27])[N:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(NC(=S)Nc1ncc(Br)nc1OCc1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=S)Nc1ncc(Br)nc1OCc1ccccc1
Yield: 99.9 %

Procedure:
Following the method of Example 1, Step C, 1-benzoyl-3-(3-(benzyloxy)-5-bromopyrazin-2-yl)thiourea (2.38 g, 5.37 mmol), and potassium carbonate (890 mg, 6.44 mmol) were reacted in ethanol (30 mL) to provide 1-(3-(benzyloxy)-5-bromopyrazin-2-yl)thiourea (1.82 g, 53%) as a light gray powder. 1H NMR (d6-DMSO) δ 9.62 (bs, 1H), 9.37 (bs, 1H), 8.73 (bs, 1H), 8.03 (s, 1H), 7.55 (d, 2H), 7.38-7.45 (m, 3H), 5.43 (s, 2H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[OH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>CC(C)=O.C(Cl)Cl>[C:4]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:15][CH2:14]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: OCCOCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)CC(=O)OCCOCCN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
20 ml of a 50% strength solution of diketene in acetone are added dropwise to 32.5 g of N-[2-(2-hydroxyethoxy)-ethyl]-4,4-diphenylpiperidine and about 0.1 g of N,N-dimethylaminopyridine in 200 ml of methylene chloride at the boiling point, with vigorous stirring. After boiling under reflux for 1 h, the solution is allowed to cool and is concentrated to constant weight under a high vacuum. The pale yellow viscous coil which remains is used for the next stage without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)=[N:5][CH:4]=[N:3]1.[CH3:16][N:17]1[C:21]([C:22]2C=CC=CC=2N)=[N:20][CH:19]=N1>>[NH:20]1[CH2:19][CH2:16][N:17]=[C:21]1[CH2:22][NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1
Reactant: Cn1ncnc1-c1ccccc1N
Reactant: Cn1ncnc1-c1ccccc1[N+](=O)[O-]
Product: Cn1ncnc1-c1ccccc1NCC1=NCCN1

Procedure:
In a fashion analogous to Example 90, 1-methyl-5-(2-nitrophenyl)-1,2,4-triazole was prepared, the nitro reduced, and the resulting 1-methyl-5-(2-aminophenyl)-1,2,4-triazole coupled with CMI to give N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(1-methyl-1H-1,2,4-triazol-5-yl)aniline.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[NH2:11][C:12]1[S:13]C=CN=1.C(N=C=S)(=O)C1C=CC=CC=1>>[S:7]1[CH:8]=[CH:9][N:10]=[C:6]1[NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:12]([NH2:11])=[S:13]
Reactant: NCCCNc1nccs1
Reactant: Nc1nccs1
Agent: O=C(N=C=S)c1ccccc1
Product: NC(=S)NCCCNc1nccs1

Procedure:
By the procedure of Example 46, reacting 2-(3-aminopropylamino)thiazole (prepared from 2-aminothiazole by the method of Example 53) with benzoyl isothiocyanate gives N-benzoyl-N'-[(3-(2-thiazolylamino)propyl]thiourea. Removing the benzoyl group by the procedure of Example 46 gives N-[3-(2-thiazolylamino)propyl]thiourea.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([NH:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])[CH3:12].[O-]CC.[Na+]>C(O)C>[C:11]([NH:14][C:15]([CH2:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])[CH3:12]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: BrCC=Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC=Cc1ccccc1)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Yield: 32.2 %

Procedure:
A solution of 5.42 g of cinnamyl bromide, 5.43 g of diethyl 2-acetamidomalonate and 1.87 g of sodium ethoxide in 70 ml of ethanol was refluxed under heating for 2 hours under a nitrogen atmosphere. The mixture was poured into 200 ml of ice water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled away. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:10-1:3) to give 2.68 g of diethyl 2-acetamido-2-(3-phenyl-2-propenyl)malonate as white crystals.
Reaction SMILES: Cl.[F:2][CH:3]([F:13])[O:4][C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1.[CH:14]([CH:16]([CH:22]=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=O>C(O)C.CCCCC>[F:2][CH:3]([F:13])[O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH:22]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=[N:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: NNc1cccc(OC(F)F)c1
Reactant: CCOC(=O)C(C=O)C=O
Agent: Cl
Solvent: CCCCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cccc(OC(F)F)c2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(3-(Difluoromethoxy)phenyl)hydrazine hydrochloride (4.2 g, 19.9 mmol; CAS 479581-64-1) was suspended in ethanol (80 ml) and cooled to 0° C. A solution of ethyl 2-formyl-3-oxopropanoate (2.87 g, 19.9 mmol; CAS 80370-42-9) in ethanol (40 ml) was added, and the reaction was stirred overnight. The solvent was removed under reduced pressure and the residue partitioned between sodium bicarbonate solution and ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated to yield an orange solid. The solid was suspended in pentane (50 ml) and stirred at 35° C. for 90 min. The suspension was cooled in an ice bath for one hour and the solid was filtered and washed with pentane. After drying 5.12 g (91%) of a yellow solid was obtained MS (ISP): 283.1 ([M+H]+).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[P:7]([O:16]CCCl)([O:12]CCCl)[O:8]CCCl.[CH2:20]([CH:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH:23]=O)[CH3:21]>C1CCCCC1.O>[CH3:1][N:2]([CH:23]([P:7](=[O:8])([OH:12])[OH:16])[CH:22]([CH2:20][CH3:21])[CH2:25][CH2:26][CH2:27][CH3:28])[C:3]([NH:5][CH3:6])=[O:4]
Reactant: CCCCC(C=O)CC
Reactant: CNC(=O)NC
Reactant: ClCCOP(OCCCl)OCCCl
Solvent: C1CCCCC1
Solvent: O
Product: CCCCC(CC)C(N(C)C(=O)NC)P(=O)(O)O

Procedure:
A mixture of 88.1g (1.0 mole) of 1,3-dimethylurea, 269.5g (1.0 mole) of tris(2-chloroethyl) phosphite, and 135g (1.05 moles) of 2-ethylhexaldehyde is warmed at 105°-110° for 2 hr, giving a clear colorless solution: 31P nmr -30.8 and -28.2 ppm (~2:1 areas). Four-fifths of the reaction mixture is dissolved in 200ml of cyclohexane containing 34.5g of H2O, and the mixture is warmed at 82° for 0.5 hr. Filtration after cooling, and extraction of the solid with hot acetonitrile gives 54.7g of white solid (100.8g more separates from the filtrate while standing): mp 184°-186° dec; 31P nmr (CD3SOCD3) -23.5 ppm(m); 1H nmr δ9.8 (broad, 2, OH), 4.4 (d of d, 1, J = 10 and 20Hz, PCH), 2.7 (s, 3, NCH3), 2.5 (s, 3, NCH3), 0.5-2.0 (broad, 15, hexyl); acidity 1.985 equiv/mole, pK1 = 1.76, pK2 = 5.29.
Reaction SMILES: [B:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7](O)=[O:8])([OH:3])[OH:2].CN.[CH3:17][N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:14][O:13][C:12]1[CH:11]=[CH:10][C:6]([C:7](=[O:8])[NH:18][CH3:17])=[CH:5][C:4]=1[B:1]([OH:3])[OH:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc(C(=O)O)cc1B(O)O
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(OC)c(B(O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.9 %

Procedure:
3-Borono-4-methoxybenzoic acid (2.5 g, 12.50 mmol) was dissolved in DMF (6 ml) and 12.50 ml methylamine (2 M solution in THF, 25 mmol) was added followed by HATU (4.75 mg, 12.5 mmol) and NMM (1.375, 12.50 mmol). The reaction mixture was stirred at RT for 20 hours and concentrated. The crude material was added to 50 ml water and extracted 3 times with EtOAc. The combined organic phases were dried (Na2SO4), filtered and concentrated. The crude material was triturated in EtOAc and filtered. The residue was purified by chromatography (Silicagel, CH2Cl2/MeOH 95:5) to give 1.92 g (7.11 mmol, 56.9% yield) of the title compound as a colorless solid. LCMS: (M+H)=210; tR=0.50 min (LC-MS 1). TLC: Rf=0.27 (CH2Cl2/MeOH 95:5). HPLC: tR=3.76 min (HPLC 3). 1H-NMR (d6-DMSO, 600.13 MHz) δ ppm 8.29 (bs, 1H), 8.03 (s, 1H), 7.87 (d, 1H), 7.85 (s, 2H) 7.02 (d, 1H), 3.84 (s, 3H), 2.75 (d, 3H).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C1CCN2C(=NCCC2)CC1>CC#N>[C:5]([O:4][C:3](=[O:9])[NH:2][O:1][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:8])([CH3:7])[CH3:6]
Reactant: CCCCCBr
Reactant: CC(C)(C)OC(=O)NO
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCONC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.8 %

Procedure:
Tert-butyl hydroxycarbamate (2.1 g, 15.77 mmol, 1 eq.) was dissolved in MeCN and bromopentane (2.73 g, 18.13 mmol, 1.15 eq.) was added followed by DBU (2.52 g, 16.56 mmol, 1.05 eq.). The reaction was stirred at room temperature for 12 h and quenched with 0.1N HCl, extracted with EtOAc, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel to give tert-butyl(pentyloxy)carbamate (3.23 g, 91% yield) as a clear oil.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18][CH3:19])[S:17][C:13]=3[CH:12]=2)[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.ClC1C=CC=C(C(OO)=[O:30])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[N:1]1[CH:2]=[C:3]([CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18]([CH3:19])=[O:30])[S:17][C:13]=3[CH:12]=2)[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: CSc1nc2ccc(Cc3cnc4cccnn34)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cc3cnc4cccnn34)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirred solution of 6-(imidazo[1,2-b]pyridazin-3-ylmethyl)-2-(methylthio)benzo[d]thiazole (350 mg, 1.1 mmol) from the previous step in DCM (30 mL) at 0° C. was added meta-chloroperbenzoic acid (194 mg, 1.1 mmol). The reaction mixture was stirred at 0° C. for 2 h. To the mixture was added saturated aq Na2S2O3 (15 mL) and the mixture was stirred for a further 0.5 h. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2 to 5% MeOH in DCM to afford 6-(imidazo[1,2-b]pyridazin-3-ylmethyl)-2-(methylsulfinyl)benzo[d]thiazole (320 mg, 87%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.33 (dd, J=4.5, 1.5 Hz, 1H), 7.91-8.00 (m, 3H), 7.62 (s, 1H), 7.54 (dd, J=8.4, 1.8 Hz, 1H), 7.03 (m, 1H), 4.52 (s, 2H), 3.05 (s, 3H); LCMS (ESI) m/z 329 (M+H)+.
Reaction SMILES: [CH2:1]([O:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH:15]=[O:16])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOCc1ccc(CO)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCCCCCCCOCc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 12.9 %

Procedure:
4-(Octyloxymethyl)benzyl alcohol (0.14 g, 0.56 mmol, from Step A) was dissolved in methylene chloride (1.5 mL) and the reaction mixture was cooled to 0° C. 4-methylmorpholine N-oxide (0.10 g, 0.84 mmol) and molecular sieves (4A) (0.25 g) were added. Tetrapropylammonium perruthenate (0.004 g, 0.011 mmol) was added and the resulting mixture was stirred for 1 h. The reaction mixture was filtered through celite. Silica gel chromatography eluting with 6% ethyl acetate/hexane gave 0.018 g of product: 1H NMR (500 MHz) δ 10.02 (s, 1H), 7.86-7.90 (m, 2H), 7.50-7.55 (m, 2H), 4.58-4.62 (s, 2H), 3.50-3.55 (m, 2H), 1.62-1.70 (m, 2H), 1.24-1.35 (m, 2H), 0.87-0.93 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([C:17]2[C:18]([CH3:27])=[N:19][C:20](S(C)(=O)=O)=[N:21][CH:22]=2)[CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O1CCOCC1>[C:11]([O:10][C:8](=[O:9])[CH2:7][O:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]=1[C:17]1[C:18]([CH3:27])=[N:19][C:20]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[N:21][CH:22]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1nc(S(C)(=O)=O)ncc1-c1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Cc1nc(N2CCOCC2)ncc1-c1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
A solution of the product from step (vii) (0.15 g) and morpholine (0.15 ml) in dioxane (3 ml) was heated at 90° C. for 24 h, cooled and the solvent evaporated under reduced pressure.
Reaction SMILES: C[O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[O:7][C:6]2=[O:15].Br>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(O)(=O)C>[OH:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[O:7][C:6]2=[O:15]
Reactant: COc1cc2c(c([N+](=O)[O-])c1OC)C(=O)OC2=O
Agent: Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Solvent: CC(=O)O
Product: COc1cc2c(c([N+](=O)[O-])c1O)C(=O)OC2=O

Procedure:
5,6-Dimethoxy-4-nitro-isobenzofuran-1,3-dione (346 mg), 48% hydrogen bromide (1.5 ml), Acetic acid (15 ml) and benzyl triethylammonium bromide (37 mg) were heated at 140° C. for 3 hours. The acetic acid and water was removed in vacuo. The remainder was filtered through silica gel using a mixture of toluene, ethyl acetate and methanol (8:1:1) as eluent. Appropriate fractions were collected and evaporated.
Reaction SMILES: [C@H]1(N[C:12]([C@@H:14]2[CH2:23]C3C(=CC(OS(C(F)(F)F)(=O)=O)=CC=3)[CH2:16][N:15]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:13])C2C(=CC=CC=2)CCC1.[NH2:39][C@@H:40]([C:69]([CH3:72])([CH3:71])[CH3:70])[C:41]([N:43]1[C@H:52]([C:53]([NH:55][C@H:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH2:59][CH2:58][CH2:57]2)=[O:54])[CH2:51][C:50]2[C:45](=[CH:46][C:47]([N+:66]([O-:68])=[O:67])=[CH:48][CH:49]=2)[CH2:44]1)=[O:42].C(OC(N(C)[C@@H](C)C(O)=O)=O)(C)(C)C>>[CH3:70][C:69]([CH3:72])([CH3:71])[C@H:40]([NH:39][C:12](=[O:13])[C@@H:14]([N:15]([CH3:16])[C:32](=[O:33])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH3:23])[C:41]([N:43]1[C@H:52]([C:53](=[O:54])[NH:55][C@H:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH2:59][CH2:58][CH2:57]2)[CH2:51][C:50]2[C:45](=[CH:46][C:47]([N+:66]([O-:68])=[O:67])=[CH:48][CH:49]=2)[CH2:44]1)=[O:42]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: CC(C)(C)[C@H](N)C(=O)N1Cc2cc([N+](=O)[O-])ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Product: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc([N+](=O)[O-])ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Yield: 97 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound D, (S)-2-((S)-2-amino-3,3-dimethylbutanoyl)-7-nitro-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (2.17 g, 4.67 mmol) and (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (Advanced ChemTech, 0.95 g, 4.67 mmol) were converted to the title compound (2.93 g, 97%). MS (ESI+) m/z 650.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][O:10]1.[Cl:27]N1C(=O)CCC1=O>C(#N)C.C(=O)([O-])O.[Na+].O>[Cl:27][C:21]1[CH:20]=[CH:19][C:18]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:17]2[C:16]=1[N:15]=[C:14]1[CH:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[O:10][CH2:11][CH2:12][N:13]21.[Cl:27][C:19]1[C:18]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:17]2[N:13]3[CH2:12][CH2:11][O:10][CH:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C:14]3=[N:15][C:16]2=[CH:21][CH:20]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCN(CC)c1cccc2nc3n(c12)CCOC3c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCN(CC)c1c(Cl)ccc2nc3n(c12)CCOC3c1ccc(Cl)cc1Cl
Product: CCN(CC)c1ccc(Cl)c2nc3n(c12)CCOC3c1ccc(Cl)cc1Cl

Procedure:
To a solution of 1-(2,4-dichlorophenyl)-N,N-diethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazol-6-amine (500 mg, 1.28 mmol) in acetonitrile (13 mL) was added N-chlorosuccinimide (171 mg, 1.28 mmol) at room temperature. After the resultant mixture was stirred at 60° C. for 5 h, the mixture was diluted with aqueous sodium hydrogen carbonate and water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 25-75% ethyl acetate/n-hexane gradient mixture and preparative HPLC eluting with a 10-100% acetonitrile/water to give 9-chloro-1-(2,4-dichlorophenyl)-N,N-diethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazol-6-amine as a colorless amorphous solid (Example 502, long retention time on HPLC, 128 mg, 0.302 mmol, 24%), and 7-chloro-1-(2,4-dichlorophenyl)-N,N-diethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazol-6-amine as a colorless amorphous solid (Example 503, short retention time on HPLC, 160 mg, 0.378 mmol, 30%)
Reaction SMILES: [CH3:1][C:2]12[O:9][CH:8]1[CH2:7][C:6]1([CH3:11])[CH2:10][CH:3]2[CH2:4][CH2:5]1.B(F)(F)F.O(CC)CC>C1(C)C=CC=CC=1>[CH3:11][C:6]12[CH2:10][CH:3]([CH2:4][CH2:5]1)[CH:2]([CH3:1])[C:8](=[O:9])[CH2:7]2
Reactant: CC12CCC(C1)C1(C)OC1C2
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1C(=O)CC2(C)CCC1C2
Temperature: 30 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
2,6-Dimethyl-3-oxa-tricyclo[4.2.1.0*2,4*]nonane (381 g, 2.51 mol, obtained as above in EXAMPLE II) was fed into a solution of boron trifluoride diethyletherate (BF3.O(C2H5)2, BF3, 35 g, 0.251 mol) in toluene (500 mL) while the pot temperature was maintained at about 30° C. and the aging process continued for 6 hours. The reaction mixture was subsequently quenched with water and washed with a Na2CO3 solution. Fractional distillation of the organic layer provided 1,4-dimethyl-bicyclo[3.2.1]octan-3-one (337 g) having a boiling point of 43° C. at a pressure of 1 mmHg.
Reaction SMILES: CO[C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:39]2[C:40]([C:45]3[CH:50]=CC=C(F)C=3)=[N:41][O:42][C:43]=2C)=NC=1.NC1CCOCC1>>[C:21]1([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:41][CH:40]4[CH2:45][CH2:50][O:42][CH2:43][CH2:39]4)=[O:27])=[CH:5][N:6]=3)=[C:16]([C:17]([F:19])([F:20])[F:18])[O:15][N:14]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Agent: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Yield: 94 %

Procedure:
As described for example 90, 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.26 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester was converted, using 4-aminotetrahydropyran instead of cyclopropylmethylamine, to the title compound (111 mg, 94%) which was obtained as a white solid. MS: m/e=448.3 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH3:7][C:8]([S-:11])([CH3:10])[CH3:9].[Na+]>CN(C=O)C>[CH3:7][C:8]([S:11][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])([CH3:10])[CH3:9]
Reactant: BrCCCCBr
Reactant: CC(C)(C)[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)SCCCCBr
Temperature: 70 °C
Yield: 21 %

Procedure:
A solution of 1,4-dibromobutane (commercially available, for example, from Aldrich) (4.7 ml, 40 mmol) in DMF (10 ml) was treated with sodium 2-methyl-2-propanethiolate (commercially available, for example, from Aldrich) (3.36 g, 30 mmol) and the mixture was heated for 23 h at 70° C. The mixture was allowed to cool to room temperature, and partitioned between water and EtOAc. The organic solution was washed with water (×4), aqueous sodium bicarbonate solution, brine, dried (MgSO4), and evaporated. The residue was purified by flash column chromatography on silica (200 g) eluting with 0-50% EtOAc-cyclohexane to give the title compound (1.4 g, 21%): 1H NMR δ (CDCl3) 3.46 (2H, t, J=7 Hz), 2.96 (2H, t, J=7 Hz), 2.15-2.03 (4H, m), 1.44 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([Li])CCC.CCOCC.[Mg+2].[Br-].[Br-].[CH:25]1([CH:28]=[O:29])[CH2:27][CH2:26]1>O1CCCC1.O>[CH:25]1([CH:28]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)[OH:29])[CH2:27][CH2:26]1
Reactant: O=CC1CC1
Reactant: COc1cccc2ccoc12
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2cc(C(O)C3CC3)oc12
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 7-methoxybenzofuran (2.0 g) in tetrahydrofuran (30 ml) cooled to -60° C. under an atmosphere of nitrogen was added dropwise n-butyllithium (1.6M in hexanes, 8.9 ml). After stirring at -60° C. for 10 minutes, magnesium bromide diethyl etherate (3.8 g) was added in single portion and the reaction mixture stirred at -50° C. for 10 minutes. After cooling to -78° C., cyclopropane carboxaldehyde (1.0 ml) was added in a single portion and the mixture allowed to warm slowly to room temperature and stirred for 1 h. Water (2 ml) was added and the tetrahydrofuran removed in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml); the aqueous layer was extracted with ethyl acetate (50 ml); the organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 0-5% methanol in dichloromethane afforded the title compound as a yellow gum (1.88 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1.BrC1C=CC([Cl:31])=C(Cl)C=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([Cl:31])=[C:14]([Cl:18])[CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Reactant: Clc1ccc(Br)cc1Cl
Product: O=C(O)Cc1c(C(=O)c2ccc(Cl)c(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1) and 1-bromo-3,4-dichlorobenzene.