Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=1>>[CH3:24][O:23][C:20]1[N:21]=[CH:22][C:17]([NH:16][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:18][CH:19]=1
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Reactant: COc1ccc(N)cn1
Product: COc1ccc(Nc2ncccc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 22 using 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine and 5-amino-2-methoxypyridine (Aldrich), and isolated as a yellow solid (80%). LCMS (API-ES) m/z 310 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 11.74 (br. s., 1H) 8.77 (dd, J=5.02, 2.51 Hz, 1H) 8.53 (br. s., 1H) 8.29 (br. s., 1H) 8.08-8.23 (m, 1H) 7.84 (br. s., 1H) 7.71 (br. s., 1H) 6.88 (ddd, J=7.78, 4.27, 4.02 Hz, 1H) 6.82 (dd, J=8.78, 4.27 Hz, 1H) 3.84 (d, J=5.02 Hz, 3H) 2.42 (d, J=4.02 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[C:18]([CH3:23])=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]=1[CH3:34]>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[C:18]([CH3:23])=[N:19][N:20]([CH3:22])[CH:21]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:27][C:26]=1[CH3:34]
Reactant: Cc1cc(B(O)O)ccc1Cl
Reactant: Cc1nn(C)cc1C(=O)Nc1cnc(OCC(F)(F)F)c(Br)c1
Product: Cc1cc(-c2cc(NC(=O)c3cn(C)nc3C)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 39, using 1,3-dimethyl-1H-pyrazole-4-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 58 a) and B-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; LC-MS (UV peak area/ESI) 96.1%, 439.1154 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.C([N:21]([CH2:24][CH3:25])CC)C.[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>>[C:24]([C:25]1[CH:11]=[CH:10][C:18]([C:17]2[CH:28]=[CH:27][C:26]([C:30]([N:15]3[C:16]4[CH:17]=[C:18]5[C:5]6([CH2:8][O:9][C:10]5=[CH:11][C:12]=4[CH2:13][CH2:14]3)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[O:29])=[CH:12][CH:16]=2)=[C:5]([CH3:6])[CH:4]=1)#[N:21]
Reactant: C1CCOC1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: CCN(CC)CC
Product: Cc1cc(C#N)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Temperature: 25 °C
Yield: 34 %

Procedure:
A stirred suspension of 4'-cyano-2'-methylbiphenyl-4-carboxylic acid (D16) (0.3 g, 1.3 mmole) in dichloromethane (10 ml) at room temperature under argon was treated with oxalyl chloride (0.12 ml, 1.43 mmole), followed by DMF (1 drop). The mixture was stirred for 2 h, then concentrated in vacuo to leave the acid chloride as a pale yellow solid. This was dissolved in dry THF (8 ml) and added to a stirred solution of 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) (0.3 g, 1.3 mmole) and triethylamine (0.35 ml, 2.6 mmole) in dry THF (10 ml) at 5° C. under argon. The reaction mixture was allowed to warm to room temperature and then concentrated in vacuo. The residue was taken up in 10% Na2CO3 solution (20 ml) and extracted with EtOAc (2×30 ml). The combined extract was dried (Na2SO4) concentrated in vacuo and the residue chromatographed on silica gel eluting with 1% methanol/dichloromethane to give the title compound (0.2 g, 34%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH:36]1([C:39]2[C:47]3[C:46]([NH2:48])=[CH:45][CH:44]=[CH:43][C:42]=3[N:41]([CH2:49][C:50]3[CH:54]=[CH:53][N:52]([CH2:55][CH3:56])[N:51]=3)[N:40]=2)[CH2:38][CH2:37]1>CN1C(=O)CCC1>[CH:36]1([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][C:46]=3[NH:48][C:20]([C:17]3[N:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:12][C:13]4=[N:19][CH:18]=3)=[O:22])[N:41]([CH2:49][C:50]3[CH:54]=[CH:53][N:52]([CH2:55][CH3:56])[N:51]=3)[N:40]=2)[CH2:37][CH2:38]1
Reactant: CCn1ccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: CCn1ccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (100 mg, 0.316 mmol; prepared as in Example 56, step A) was added NMP (60 mL). The reaction mixture was cooled to 0° C. and 2,4,6-trichlorobenzoyl chloride (50.4 μL, 0.316 mmol) was added dropwise. The cold bath was removed once the addition was complete. The reaction mixture was stirred for 1 hour. The reaction mixture became cloudy. 3-Cyclopropyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-amine (59.4 mg, 0.211 mmol) was added and the mixture was heated to 88° C. for 11 hours. The mixture was cooled to ambient temperature. Vacuum distillation was set up and NMP was removed until the reaction mixture became a thick oily residue, to which 10% NaOH aqueous solution (100 mL) was added and the resulting clear solution was stirred at 80° C. for 30 minutes. The mixture was cooled to ambient temperature and extracted with DCM. The organic phases were combined, dried (Na2SO4) and concentrated under vacuum (bath temperature at 80° C. to remove left over NMP) to a thick residue, which was triturated with Et2O (500 mL) to give the final product (80 mg). MS (ES+APCI) m/z=568 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12]([Br:15])[C:13]#[CH:14]>C(O)CCC>[BrH:15].[NH:1]=[C:2]1[N:6]([CH2:14][C:13]#[CH:12])[C:5]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:4]=2[S:3]1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: C#CCBr
Solvent: CCCCO
Product: Br
Product: C#CCn1c(=N)sc2cc(F)ccc21
Temperature: 100 °C
Yield: 62.1 %

Procedure:
In 800 ml of n-butanol was dissolved 25.0 g of 2-amino-6-fluorobenzothiazole. With heating at 100° C., 25.0 g of propargyl bromide was dropwise added to the solution. After completion of the dropwise addition, the mixture was heated for 4 hours. The precipitated crystals were taken out by filtration and recrystallized from water to give 26.5 g of 2-imino-6-fluoro-3-propargylbenzothiazole hydrobromide. The hydrobromide, 26.5 g, was added to a mixture of 2.54 g of sodium and 70 ml of ethanol at room temperature followed by refluxing for one hour. After completion of the reaction, the solvent was removed and, water and ethyl acetate were added to the residue followed by separation. After 2N hydrochloric acid was added to the residue obtained from the ethyl acetate phase, water was evaporated to give 20.7 g of 7-fluoro-2-methylimidazo[2,1-b]benzothiazole hydrochloride.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23](=[O:24])[NH:22][C:21]3[C:16]2=[N:17][C:18]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)=[N:19][C:20]=3[C:25]([O:27]CC)=O)[CH2:11][CH2:10]1)=O)(C)(C)C.[NH2:37]C1C(C(OCC)=O)=NC(C2C=CC=C(O)C=2)=NC=1N[C@H]1CC[C@H](NC(OC(C)(C)C)=O)CC1>ClCCl>[NH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23](=[O:24])[NH:22][C:21]3[C:16]2=[N:17][C:18]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)=[N:19][C:20]=3[C:25]([NH2:37])=[O:27])[CH2:11][CH2:10]1
Reactant: CCOC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CCOC(=O)c1nc(-c2cccc(O)c2)nc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1N
Solvent: ClCCl
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2[C@H]1CC[C@H](N)CC1

Procedure:
Ethyl 9-(trans-4-(tert-butoxycarbonylamino)cyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-6-(trans-4-(tert-butoxycarbonylamino)cyclohexylamino)-2-(3-hydroxyphenyl)pyrimidine-4-carboxylate (0.150 g, 0.317 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.514 g, 3.17 mmol) in dichloromethane (10 mL) were reacted according to General Procedure F and purified via biotage chromatography (0 to 60% EtOAc in hexanes) to afford the title compound (0.070 g, 44%). MS (ESI) m/z 498[M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8](O)=O)=[CH:4][CH:3]=1.[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17].C([O-])(O)=[O:20].[Na+]>O>[NH:17]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:18]=[C:8]1[C:5]1[N:6]=[N:7][C:2]([OH:20])=[CH:3][CH:4]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: Nc1ccccc1N
Agent: [Na+]
Solvent: O
Product: Oc1ccc(-c2nc3ccccc3[nH]2)nn1
Temperature: 160 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
A mixture of 6-chloropyridazine-3-carboxylic acid (0.800 g, 5.060 mmol), o-phenylenediamine (0.550 g, 5.080 mmol) amd polyphosphoric acid (25 g) was heated at 150-170° C. with stirring for 3 hours. Water was added to the reaction mixture, and the resulting solution was neutralized with NaHCO3, and extracted with ethyl acetate. The organic phase was dried and evaporated to afford 6-(1H-benzoimidazol-2-yl)pyridazin-3-ol was isolated as a white solid in 31% yield (0.322 g, 1.570 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3)[C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][CH:14]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][CH:14]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Br)cncc3c2)cc1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1cncc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a microwave vial charged with (2-methoxyphenyl)boronic acid (25.6 mg, 0.168 mmol), 4-bromo-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-7-sulfonamide (Intermediate PPPP) (75 mg, 0.153 mmol), and potassium phosphate tribasic (38.0 μl, 0.459 mmol) was added dioxane (613 μl) and water (204 μl). The mixture was purged with argon prior to the addition of 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (10.83 mg, 0.015 mmol). The mixture was irradiated at 100° C. in a microwave for 30 min. The organics were decanted, the aqueous rinsed with EtOAc and the organics combined and dried under reduced pressure. The crude material was dissolved in DCM (1.5 ml) and TFA (0.5 ml) was added and the mixture shaken at room temperature for 2 hrs. The resulting mixture was dried under reduced pressure and purified with a 25 g Interchim HP spherical silica column (Interchim, Mouintlucon, France) (15 μm) ramping EtOAc in heptane (0 to 100%, 10% DCM throughout) with product eluting at 100% polar eluent to afford 4-(2-methoxyphenyl)-N-(thiazol-2-yl)isoquinoline-7-sulfonamide (40 mg, 0.101 mmol, 65.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.87 (d, J=4.60 Hz, 1H) 7.08-7.16 (m, 1H) 7.22 (d, J=8.22 Hz, 1H) 7.25-7.35 (m, 2H) 7.48-7.55 (m, 1H) 7.61 (d, J=8.90 Hz, 1H) 8.00 (dd, J=8.85, 1.91 Hz, 1H) 8.48 (s, 1H) 8.71 (d, J=1.76 Hz, 1H) 9.55 (s, 1H) 12.87 (br. s., 1H). m/z (ESI) 398.2 (M+H)+.
Reaction SMILES: O1CCO[CH2:3][CH2:2]1.Br[C:8]1[CH:33]=[N:32][C:11]2[O:12][C:13]([CH3:31])([CH3:30])[C:14](=[O:29])[N:15]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[CH:9]=1.CCCCCC.C([Zn]CC)C>O>[CH2:2]([C:8]1[CH:33]=[N:32][C:11]2[O:12][C:13]([CH3:30])([CH3:31])[C:14](=[O:29])[N:15]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[CH:9]=1)[CH3:3]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)Oc3ncc(Br)cc32)CC1
Agent: CC[Zn]CC
Solvent: O
Solvent: CCCCCC
Product: CCc1cnc2c(c1)N(C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)C(C)(C)O2
Reaction time: 8 h

Procedure:
At room temperature, to a 1,4-dioxane solution (10.0 ml) of tert-butyl 4-(7-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (Example 52-1) (150 mg) was added a [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (69.5 mg), and then a hexane solution (1 M, 0.681 ml) of diethyl zinc was added dropwise, followed by stirring overnight. The reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (84.8 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[NH:1]([CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccccc1)C(=O)OCC

Procedure:
Freshly distilled aniline (46.5 g) and diethyl ethoxymethylene malonate (108 g) were heated together on a steam bath for two hours. The ethanol formed in the reaction was then evaporated off under vacuum to give the intermediate diethyl (anilinomethylene)malonate, m.p. 48° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14](Cl)(=[O:16])=[O:15])([O-:7])=[O:6]>C(Cl)Cl>[CH:1]1([NH:4][S:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N+:5]([O-:7])=[O:6])(=[O:15])=[O:16])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NC1CC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CC1
Reaction time: 12 h
Yield: 88 %

Procedure:
To a −78° C. mixture of cyclopropylamine (10 g, 1.75 mmol) in CH2Cl2 (100 mL) was added a solution of 2-nitrobenzene sulfonyl chloride (22.1 g, 85.7 mmol) and the mixture was stirred for 12 h. The mixture was washed with 1N HCl dried over MgSO4 then concentrated to give 18.7 g, (88%) of a N-Cyclopropyl-2-nitro-benzenesulfonamide as a tan solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:16]C(=O)OCC3C4C=CC=CC=4C4C3=CC=CC=4)[CH:14]=2)[C:9](=[O:34])[N:8]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:7]=1[CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:2][CH2:3][CH3:4].N1CCCC1.O>CN(C)C=O>[C:44]([O:43][C:41](=[O:42])[NH:40][CH2:39][C:7]1[N:8]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:9](=[O:34])[C:10]2[C:15]([C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)([CH3:47])([CH3:45])[CH3:46]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(NC(=O)OCC3c4ccccc4-c4ccccc43)cc12
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(N)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 9H-fluoren-9-ylmethyl 4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinylcarbamate (0.45 g, 0.7 mmol) in N,N-dimethylformamide (10 ml) was added pyrrolidine (0.5 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(6-amino-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.23 g, 79.3%) as crystals.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:10])[CH2:2][CH3:3].[N+:11]([O-])([OH:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[N+:11]([C:8]1[CH:7]=[CH:6][N+:5]([O-:10])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=1)([O-:13])=[O:12]
Reactant: CCCc1cccc[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCc1cc([N+](=O)[O-])cc[n+]1[O-]
Temperature: 71 °C
Yield: 49 %

Procedure:
A mixture of 2-n-propylpyridine-N-oxide (137.2 g, 1.0 mol) in 200 ml of sulfuric acid (sp. gr. 1.84) was stirred in an ice-salt bath and 320 ml of nitric acid (sp. gr. 1.52) was added. The mixture was carefully heated to 70-72° C. and reacted for 22 hours. The reaction mixture was cooled and poured onto ice and, with stirring, neutralized with portions of sodium carbonate (500 g). The resulting precipitate was collected, washed with water and dried. The dried substance was slurred in 1 liter of dichloromethane and anhydrous sodium sulfate was added. The mixture was filtered and the solvent was evaporated. The yellow residue from evaporation of the dichloromethane solution was dried to afford 89.2 g (49%) of 4-nitro-2-n-propylpyridine-N-oxide. M.p. 89-91° C. 1H-NMR (CDCl3, 200 MHz) δ: 1.10 (t, 3H); 1.70 (sext, 2H); 2.94 (t, 2H); 7.96 (dd, 1H); 8.08 (dd, 1H); 8.30 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([C:24](=[O:25])[C:23]3[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:28][CH:27]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Cc1ccccc1CN2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Cc2cc(Cl)ccc21
Yield: 68.9 %

Procedure:
A mixture of 2.05 g of 2-chloro-6,11-dihydro-5H-dibenz[b,e]azepine, 2.15 g of 4-nitrobenzoyl chloride, 1.50 g of N,N-diisopropylethylamine, 54 mg of 4-(dimethylamino)pyridine in 15 ml of dichloromethane is refluxed for 18 hours. The mixture is cooled and washed with H2O, 1N HCl, 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated and the residue recrystallized from dichloromethane-hexane to give 2.33 g of crystals, m.p. 198°-201° C.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[H-].[Na+].C1COCC1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:30])[CH2:25][CH2:24][CH2:23]2>C1COCC1.CCOCC.CC(O)=O>[CH2:8]([O:7][C:3]([CH:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([O:19][CH3:18])[CH:21]=2)[C:26]1=[O:30])=[O:10])[CH3:9]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Yield: 106.5 %

Procedure:
NaH (3.4 g, 60% in mineral oil, 83.3 mmol) was washed with hexanes (3×70 mL) and THF (1×30 mL) in an oven dried 3 neck round-bottomed flask. Diethyl carbonate (5.5 mL, 45.4 mmol) was added to the NaH/THF suspension in anhydrous THF (20 mL) and the slurry was heated at reflux under N2. 6-Methoxy-1-tetralone (4 g, 22.7 mmol) in THF (40 mL) was added dropwise via an addition funnel to the suspension at reflux. The reaction mixture was then heated at reflux for 2 days. The solution was cooled to room temperature and glacial AcOH (3.6 mL) was added in a dropwise manner. Et2O (150 mL) was then added and the organic layer was washed with saturated NaCl solution (5×25 mL), dried (MgSO4), and concentrated under reduced pressure to provide a crude brown oil (6.0 g). The oil was subjected to medium pressure chromatography on silica (CHCl3) to provide a dark oil which solidified upon standing (5.17 g, 91.8% yield). The solid was recrystallized from EtOAc/hexane to provide a white solid. mp 58-60° C. 1H-NMR (300 MHz, CDCl3) δ 1.27-1.36 (t, 3H), 2.20-3.56 (m, 5H), 3.85 (s, 3H), 4.23-4.28 (m, 2H), 6.70 (s, 1H), 6.77-6.85 (d, 1H), 7.72-8.03 (d, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[C:22]([N:24]3[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[N:26]=[N:25]3)[CH:21]=[CH:20][C:19]=2[CH3:32])=[O:17])=[C:12]([CH3:33])[CH:11]=1.BrC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.NC1C=C([NH:66][C:67](=[O:69])[CH3:68])C=CC=1>>[OH:31][CH2:30][CH2:29][C:27]1[N:26]=[N:25][N:24]([C:22]2[CH:21]=[CH:20][C:19]([CH3:32])=[C:18]([CH:23]=2)[C:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:3]3[CH:4]=[C:5]([NH:66][C:67](=[O:69])[CH3:68])[CH:6]=[CH:7][CH:2]=3)=[CH:11][C:12]=2[CH3:33])=[O:17])[CH:28]=1
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Agent: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: CC(=O)Nc1cccc(Nc2ccc(C(=O)c3cc(-n4cc(CCO)nn4)ccc3C)c(C)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and N-(3-amino-phenyl)-acetamide (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using NH3(aq.)/MeOH/DCM 0:0:100, 1:9:90 as the eluent to afford the title compound as yellow solid. 13C NMR (DMSO-d6) δ 196.1, 168.2, 147.9, 145.6, 142.4, 142.0, 141.2, 140.1, 135.1, 135.0, 134.3, 131.9, 129.3, 126.0, 120.6, 120.2, 118.2, 117.6, 114.2, 112.7, 111.1, 110.0, 60.1, 29.1, 24.0, 22.1, 18.7
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.[OH-:14].[Na+].[NH2:16]O.Cl>>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N:16][OH:14]
Reactant: O=Cc1ccccc1OC(F)(F)F
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: ON=Cc1ccccc1OC(F)(F)F
Yield: 94 %

Procedure:
In a similar manner as described in Preparation Example 1, by using 2-(trifluoromethoxy)benzaldehyde (38.03 g, 200.0 mmol), sodium hydroxide (12.00 g, 300.0 mmol) and hydrochloric acid hydroxylamine (16.6 g, 240 mmol), a white solid required compound (38.67 g, 188 mmol, 94%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:18][C@:19]([C:24]2[O:25][C@@H:26]([CH3:31])[C@H:27]([CH2:29][CH3:30])[N:28]=2)([CH3:23])[CH2:20][CH:21]=[CH2:22])[C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)O)[CH:5]=[CH:6][CH:7]=1.N1C(C)=CC=CC=1C.[F:40][C:41]([F:54])([F:53])[S:42]([O:45]S(C(F)(F)F)(=O)=O)(=[O:44])=[O:43]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[O-:45][S:42]([C:41]([F:54])([F:53])[F:40])(=[O:44])=[O:43].[CH2:20]([C@@:19]1([CH3:23])[CH2:18][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N+:28]2[C@@H:27]([CH2:29][CH3:30])[C@H:26]([CH3:31])[O:25][C:24]1=2)[CH:21]=[CH2:22]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)[C@@H](O)c1ccc(Cl)cc1)C1=N[C@@H](CC)[C@H](C)O1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1O[C@@H](C)[C@@H]2CC
Product: O=S(=O)([O-])C(F)(F)F
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1R,2R,4S)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-4-((4S,5S)-4-ethyl-5-methyl-4,5-dihydrooxazol-2-yl)-4-methylhept-6-en-1-ol (80 mg, 0.174 mmol) in CH2Cl2 (1737 μl) at −50° C. was added 2,6-lutidine (46.4 μl, 0.400 mmol) followed by trifluoromethanesulfonic anhydride solution, 1 M in methylene chloride (191 μl, 0.191 mmol). The reaction was stirred at −50° C. for 30 min and then treated with an additional 25 uL of trifluoromethanesulfonic anhydride solution, 1 M in methylene chloride, then 2 mL of sat. CuSO4. The reaction was warmed to rt and extracted with dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated. Purification by column chromatography using 40 to 80% acetone in hexanes afforded (2S,3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,8-dimethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium triflate.