Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH:15]([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH2:16][NH2:17])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([CH:12]1[CH2:14][CH2:13]1)[C:18]1[CH:19]=[N:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccc(C(F)(F)F)nc1)C1CC1
Product: O=C(NCC(c1ccc(C(F)(F)F)nc1)C1CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine. LCMS (MH+): m/z=403.1, tR (minutes, Method D)=0.79
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:16][CH2:17][CH3:18])[CH2:10][C:11]([O:13]CC)=[O:12])=[CH:4][C:3]=1[O:19][CH3:20].[OH-].[Na+]>C1COCC1.CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:16][CH2:17][CH3:18])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: CCCC(CC(=O)OCC)Cc1ccc(F)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC(CC(=O)O)Cc1ccc(F)c(OC)c1
Yield: 99.6 %

Procedure:
Ethyl ester (131) (2.14 g, 7.58 mmol) was saponified with 1 N NaOH in THF and EtOH to give 1.92 g (˜100%) of the title compound (132) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.88 (t, J=7.0 Hz, 3H), 1.25-1.45 (m, 4H), 2.05-2.20 (m, 1H), 2.20-2.35 (m, 2H), 2.45-2.55 (m, 1H), 2.60-2.70 (m, 1H), 3.87 (s, 3H), 6.64-6.70 (m, 1H), 6.76 (dd, J1=8.2 Hz, J2=1.8 Hz, 1H), 6.96 (dd, J1=11.3 Hz, J2=8.2 Hz, 1H). LCMS (ESI): m/z 253 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2I)[O:9][C:8]1=[O:24].[CH:34]([C:37]1[CH:38]=[CH:39][C:40]([O:46][CH3:47])=[C:41](B(O)O)[CH:42]=1)([CH3:36])[CH3:35]>>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[C:41]2[CH:42]=[C:37]([CH:34]([CH3:36])[CH3:35])[CH:38]=[CH:39][C:40]=2[O:46][CH3:47])[O:9][C:8]1=[O:24]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: C[C@@H]1[C@@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@H]1OC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
Following the procedure described in EXAMPLE 81, 41 mg of (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one and 17 mg of (5-isopropyl-2-methoxyphenyl)boronic acid gave title compound. Mass spectrum (ESI) 620.4 (M+1). 1H NMR signals are doubled because of atropoisomerism. 1H NMR (500 MHz, CDCl3): δ 7.53-7.80 (m, 5H), 7.33 (d, J=8 Hz, 1H), 7.21-7.29 (m, 1H), 7.00, 6.76 (d, J=2.5 Hz, 1H), 6.91, 6.86 (d, J=8.5 Hz, 0.4H), 5.15, 5.10 (d, J=4.5 Hz, 1H), 4.80, 4.74 (d, J=16 Hz, 1H), 4.25, 4.21 (d, 16 Hz, 1H), 3.76 (s, 2H), 3.49 (s, 1H), 3.43 (m, 0.4H), 3.18 (m, 0.5H), 2.77-2.98 (m, 1H), 1.24 (m, 3H), 1.16 (m, 3H), 0.78, 0.61 (d, J=6.5 Hz, 3 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][C:3]=1[CH3:10].[CH2:11]([O:13][P:14]([CH2:19][CH:20]1[CH2:22][O:21]1)(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12].[Cl-].[NH4+]>C1COCC1>[CH2:16]([O:15][P:14]([CH2:19][CH:20]([OH:21])[CH2:22][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:10])[CH:4]=1)(=[O:18])[O:13][CH2:11][CH3:12])[CH3:17]
Reactant: CCOP(=O)(CC1CO1)OCC
Reactant: Cc1cc([Mg]Br)ccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOP(=O)(CC(O)Cc1ccc(F)c(C)c1)OCC
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
To a solution of 4-fluoro-3-methylphenylmagnesium bromide (0.5M in Et2O, 15.5 mL, 7.75 mmol) in THF (10 mL) at −30° C. was added Cul (196 mg, 1.03 mmol) and the reaction mixture was stirred for 10 minutes. The reaction mixture was warmed to −15° C. and oxiranylmethyl-phosphonic acid diethyl ester (1 g, 5.2 mmol) in THF (10 mL) was added. The reaction mixture was stirred at 0° C. for 2 h. Saturated aqueous ammonium chloride was added and the product was extracted into EtOAc. The organic solution was dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (20% EtOAc in hexanes to 70% EtOAc in hexanes) provided [3-(4-fluoro-3-methyl-phenyl)-2-hydroxy-propyl]-phosphonic acid diethyl ester (1.37 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:39]([CH3:40])[CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:41])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48]OS(C)(=O)=O)[CH:46]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:54][NH:55][CH3:56]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:39]([CH3:40])[CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:41])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][N:55]([CH3:56])[CH3:54])[CH:46]=2)[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CNC
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOS(C)(=O)=O)c4)c4ccccc43)cn12
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCN(C)C)c4)c4ccccc43)cn12
Temperature: 50 °C
Reaction time: 24 h
Yield: 28.8 %

Procedure:
To a solution of Intermediate 124c (0.13 mmol) in THF (2.5 mL) was added dimethylamine (2M in MeOH, 1.3 mL, 2.6 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 2-10% [2M NH3 in MeOH] in DCM, followed by MDAP (Method 7) purification, to give the title compound (26 mg, 29%). LCMS (Method 5): Rt 3.68 min, m/z 694 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.55 (3H, d, J=6.2 Hz), 0.58 (3H, d, J=6.2 Hz), 1.20 (9H, s), 1.34-1.54 3H, m), 1.63-1.68 (2H, m), 1.72-1.86 (2H, m), 1.89-1.97 (1H, m), 2.01-2.07 (2H, m), 2.23 (6H, br s), 2.77 (2H, br s), 3.08-3.18 (2H, m), 4.22 (2H, br s), 4.80 (1H, dt, J=8.6, 5.6 Hz), 5.49 (1H, t, J=4.3 Hz), 6.22 (1H, s), 7.11 (1H, d, J=8.6 Hz), 7.16 (1H, dd, J=9.8, 2.2 Hz), 7.19-7.25 (1H, m), 7.28-7.33 (3H, m), 7.60 (1H, s), 7.62 (1H, d, J=9.6 Hz), 7.84 (1H, d, J=1.9 Hz), 7.98 (1H, s), 8.02 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[C:13]([CH2:25][CH2:26][OH:27])=[N:12][C:11]=2[CH:28]([CH3:30])[CH3:29])[CH:5]=[C:6]([Cl:8])[CH:7]=1>C(OCC)(=O)C.[Pt]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:11]([CH:28]([CH3:30])[CH3:29])[N:12]=[C:13]2[CH2:25][CH2:26][OH:27])=[CH:17][CH:18]=1
Reactant: CC(C)c1nc(CCO)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)c1nc(CCO)n(Cc2ccc(N)cc2)c1Sc1cc(Cl)cc(Cl)c1

Procedure:
In 10 ml of ethyl acetate was dissolved 124 mg (0.26 mmol)of the nitrobenzyl compound (126a), and 120 mg of platinum sulfided carbon was added at room temperature. H2 gas was introduced for 7 hours under stirring, and the mixture was worked up. The reaction mixture was filtered through Celite under reduced pressure, and the filtrate was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate), the resulting oil was treated with ether for crystallization to give Compound I-139 (yield 33%), mp 142-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:21][CH2:20][C:10]3([CH2:19][CH2:18][CH2:17][C:12]4(OCC[O:13]4)[CH2:11]3)[C:9]2=[O:22])[CH:5]=[CH:6][CH:7]=1.C1COCC1.Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:21][CH2:20][C:10]3([CH2:19][CH2:18][CH2:17][C:12](=[O:13])[CH2:11]3)[C:9]2=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N(c2cccc(Cl)c2)CCC12CCCC1(C2)OCCO1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCCC2(CCN(c3cccc(Cl)c3)C2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 162.9 %

Procedure:
To a round bottom flask was added 9-(3-chloro-phenyl)-1,4-dioxa-9-aza-dispiro[4.1.4.3]tetradecan-8-one from step 4 (0.45 g, 0.84 mmol), THF (10.2 mL), and 2N aqueous HCl (7.0 mL). After stirring at rt overnight, the reaction mixture was diluted with ethyl acetate (60 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford 0.38 g (97%) of the title compound, 2-(3-chloro-phenyl)-2-aza-spiro[4.5]decane-1,7-dion, as a white solid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ7.74 (t, J=2.0 Hz, 1H), 7.52 (ddd, J=8.3, 2.2, 1.0 Hz, 1H), 7.29 (t, J=8.1 Ha, 1H), 7.13 (ddd, J=8.1, 2.0, 1.0 Hz, 1H), 3.72-3.81 (m, 2H), 2.73 (dd, J=13.9, 1.0 Hz, 1H), 2.35-2.50 (m, 2H), 2.29 (dt, J=13.9, 1.7 Hz, 1H), 2.12-2.22 (m, 2H), 2.02-2.07 (m, 2H), 1.71-1.89 (m, 2H). ESI-MS m/z: 278 (M+H)+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[N:9]([O-])=O.[Na+].[OH-].[Na+]>C(O)(=O)C>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[N:9]1
Reactant: O=N[O-]
Reactant: Nc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: c1ccc2[nH]nnc2c1

Procedure:
In carrying out the process of the present invention, an aqueous mixture or orthophenylenediamine and acetic acid is slowly added to a cooled sodium nitrite solution and the reaction carried out for a period of one to three hours at a concentration of from about 12 to about 22 percent by weight concentration of active ingredients. The order of addition of reagents is not important, as long as one reagent is added to the other at a rate sufficient to keep the temperature of the reaction below about 25° C. The reaction is followed by neutralization of the reaction mixture to a pH of 6 to 6.5 with sodium hydroxide. The entire reaction and neutralization process is carried out at low temperature, between 5° C. and 25° C. A precipitate of 1,2,3-benzotriazole is formed, filtered and washed with cold water to yield technical grade product suitable for use in industrial applications.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:17]=2)[N:12]=1)(=O)=O.CCN(C(C)C)C(C)C.[CH:37]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38]1.O>CN(C=O)C>[CH:37]1([NH:42][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([N:13]=[CH:14][C:15]=3[C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]4[CH2:25][CH2:24]4)[N:17]=3)[N:12]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: NC1CCCC1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1)C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1cc(-c2cnn3nc(NC4CCCC4)ccc23)nc(NC2CC2)n1
Temperature: 50 °C
Yield: 28.9 %

Procedure:
To a solution of 3-[2-(cyclopropylamino)-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yl trifluoromethanesulfonate (107 mg, 0.268 mmol) in DMF (2 mL) was added DIEA (0.093 mL, 0.536 mmol) and cyclopentylamine (0.026 mL, 0.268 mmol). The reaction mixture was heated at an oil bath temperature of 50° C. for about 1 hour at which point N-phenyltrifluoromethylsulfonimide (95 mg, 0.268 mmol) was added followed by an additional portion (equivalent) of cyclopentylamine and DIEA. This was repeated two more times. The mixture was cooled to RT and water (20 mL) was added. The aqueous layer was washed with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo and purified by silica-gel column chromatography (gradient, 0-10% MeOH in CH2Cl2). The residue was suspended in EtOAc and triturated with hexanes to give the title compound as a yellow solid (26 mg, 29%). 1H-NMR (300 MHz, CDCl3) δ 8.71 (d, 1H, J=9.5 Hz), 8.17 (s, 2H), 6.89 (d, 1H, J=5.7 Hz), 6.55 (d, 1H, J=9.3 Hz), 5.92 (bs, 1H), 4.43 (m, 1H), 4.30 (m, 1H), 2.84 (m, 1H), 2.16 (m, 2H), 1.71 (m, 4H), 1.50 (m, 2H), 0.87 (m, 2H), 0.66 (m, 2H); MS (APCI) (M+H)+ 336.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH2:22][OH:23])=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([CH:13]=[CH2:14])=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([C:4]1[C:5]([CH2:22][OH:23])=[C:6]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:7]([CH2:13][CH3:14])=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:2])[CH3:3]
Reactant: C=Cc1c(C(C)C)cc(C(C)C)c(CO)c1-c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1c(C(C)C)cc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reaction time: 2 h
Yield: 101.2 %

Procedure:
The intermediate obtained in Step G (7.7 g, 24.7 mmol) was dissolved in absolute ethanol (200 mL) under argon, treated with 10% palladium on carbon (610 mg, 0.1 eq), then stirred under a hydrogen atmosphere for 2 hr. After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed and the product dried in vacuo to afford the title compound as a white solid (7.7 g, 25 mmol, 99%). 1H NMR (300 MHz, CDCl3): δ 7.32 (s, 1H), 7.15 (m, 4H), 4.33 (m, 2H), 3.39 (septet, J=7 Hz, 1H), 3.32 (septet, J=7 Hz, 1H), 2.37 (q, J=7.7 Hz, 2H), 1.29 (m, 13H), 0.92 (t, J=7.7 Hz, 3H). FAB-MS calculated for (C21H27FO) 314, found 314 (M+). mp 106-108° C. Rf=0.1 (50% dichloromethane/hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([CH3:24])[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:25]I.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([CH3:24])[N:15]=2)[CH3:25])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(Nc2nc(C)nc3ccccc23)cc(OC)c1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(N(C)c2nc(C)nc3ccccc23)cc(OC)c1OC

Procedure:
The title compound was prepared from (3,4,5-trimethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (232 mg, 0.71 mmol), methyl iodide (0.07 ml, 1.08 mmol), sodium hydride (43 mg, 1.08 mmol, 60% oil dispersion) in DMF similar to example 49 to give 65 mg (27%) of white solids. 1H NMR (CDCl3): 7.75 (d, J=8.4 Hz, 1H), 7.58-7.53 (m, 1H), 7.11-7.00 (m, 2H), 6.39 (s, 2H), 3.88 (s, 3H), 3.73 (s, 6H), 3.62 (s, 3H), 2.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:15])[CH:13]=[CH2:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2ccccc12
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc2c(Cl)cccc2c1
Yield: 113.6 %

Procedure:
1-chloronaphthalene (183 mg), acryloyl chloride (120 mg), and aluminium chloride (150 mg) were reacted in dichloromethane (1.5 mL) at from −40° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (277 mg).
Reaction SMILES: [CH3:1][N:2]([C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=1[CH2:40][C:41](O)=[O:42].Cl.CN(C)CCCN=C=NCC.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=1[CH2:40][C:41]([N:13]1[CH2:14][CH2:15][CH:10]([C:7]2[S:8][CH:9]=[C:5]([C:3]([N:2]([CH3:1])[C@@H:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][CH3:18])=[O:4])[N:6]=2)[CH2:11][CH2:12]1)=[O:42]
Reactant: Cc1ccc(C)c(CC(=O)O)c1
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCNCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-N-[(1R)-1-phenylpropyl]-2-(4-piperidinyl)-4-thiazolecarboxamide (i.e. the product of Example 1, Step E) (206 mg, 0.6 mmol) was dissolved in 4 mL of dry dichloromethane. To this reaction mixture was added triethylamine (90 μL, 0.65 mmol), 2,5-dimethylbenzeneacetic acid (98 mg, 0.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (125 mg, 0.65 mmol) and a catalytic amount of 4-(dimethylamino)pyridine (˜1 mg). The mixture was shaken overnight at ambient temperature, passed through a 5 mL capacity ChemEluten™, diatomaceous filter tube, pretreated with 3 mL of 1 N aqueous hydrochloric acid solution and eluted with 2 column volumes of dichloromethane. The dichloromethane solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using acetone to give 276 mg of the title product, a compound of the present invention as a light yellow oil.
Reaction SMILES: ClC1C=CC=CC=1.[CH2:8]([N:15]1[C:19](=[O:20])[CH:18]2[CH:21]([CH3:34])[CH:22]=[CH:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH:17]2[C:16]1=[O:35])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(OCC)(=O)C>[CH2:8]([N:15]1[C:19](=[O:20])[C:18]2=[C:21]([CH3:34])[CH:22]=[CH:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])=[C:17]2[C:16]1=[O:35])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC1C=CC(c2ccccc2[N+](=O)[O-])C2C(=O)N(Cc3ccccc3)C(=O)C12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2[N+](=O)[O-])c2c1C(=O)N(Cc1ccccc1)C2=O
Temperature: 25 °C
Yield: 40.4 %

Procedure:
30 ml of chlorobenzene was added to a mixture of 5.0 g of N-benzyl-3-methyl-6-(2-nitrophenyl)-1,2,3,6-tetrahydrophthalimide and 7.0 g of DDQ. The mixture was refluxed for 8 hours, then cooled to room temperature. Thereto was added 100 ml of ethyl acetate. The resulting mixture was washed with aqueous 10% potassium carbonate solution and an aqueous saturated sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=100/1 to 80/1), followed by recrystallization from ethanol to obtain 2.0 g (yield: 40%) of N-benzyl-3-methyl-6-(2-nitrophenyl)phthalimide as light yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[N:17]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:37]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:40]([O:39][C:37]([N:47]1[CH2:52][CH2:51][N:50]([C:24]2[CH:25]=[CH:26][C:21]([C:18]3[N:17]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:16]([CH:12]4[CH2:13][CH2:14][CH2:15][N:11]4[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:36])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=3)=[CH:22][CH:23]=2)[CH2:49][CH2:48]1)=[O:38])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)n1COCC[Si](C)(C)C)C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)n1COCC[Si](C)(C)C)C(C)C
Temperature: 110 °C
Reaction time: 18 h
Yield: 12.8 %

Procedure:
(1-{2-[5-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1033 mg, 1.8 mmol) and 4-Cbz-piperazine (588 mg, 2.7 mmol) in toluene (9 mL) were treated with Pd(OAc)2 (20 mg, 0.09 mmol), BINAP (110 mg, 0.1 mmol), and NaOtBu (428 mg, 4.45 mmol). The mixture was stirred in a sealed tube at 110° C. for 18 hours. The solution was concentrated, diluted with EtOAc (50 mL), and washed with saturated NaHCO3 (20 mL), H2O (20 mL), and brine (20 mL). The solution was dried over MgSO4 and subjected to a 120 g SiO2 COMBIFLASH column (0-100% EtOAc-hexanes gradient) to afford 4-{4-[2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-phenyl]-piperazine-1-carboxylic acid benzyl ester (166 mg, 13%): MS (ESI) m/z 719 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[N:7][CH:8]=1.[I-:18].[K+]>CC(C)=O.C(Cl)Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:5]2[CH:6]=[N:7][CH:8]=[C:3]([CH2:2][I:18])[CH:4]=2)=[O:10])=[CH:12][CH:13]=1
Reactant: O=C(c1ccc(F)cc1)c1cncc(CCl)c1
Reactant: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(c1ccc(F)cc1)c1cncc(CI)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-chloromethyl-pyridin-3-yl)-(4-fluoro-phenyl)-methanone (1J) (220 mg, 0.88 mmol) in 5 mL of acetone at room temperature is added potassium iodide (590 mg, 3.6 mmol). After being stirred at room temperature for 3 hours, the reaction mixture is diluted with 50 mL of CH2Cl2 and washed with 5 mL of water. After concentration, the residue is dissolved in 15 mL of CH2Cl2 and washed with 2 mL of saturated sodium hyposulfite. After being dried, the solution was concentrate to give a 80/20 mixture (by 1H NMR) of (4-fluoro-phenyl)-(5-iodomethyl-pyridin-3-yl)-methanone (1F) and the starting chloride (1J) as light yellow solid that is used without further purification for next step reaction. MS (ESI) m/e 342 (M+H+).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=O)=[N:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[N:17][N:16]=2)[CH:15]=1
Reactant: CC(C)NC(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Nc1nnc2ccc(F)cn12
Reaction time: 16 h
Yield: 82.2 %

Procedure:
Hexachloroethane (1.77 g, 7.75 mmol) was added portionwise to a solution of Intermediate 8a 822 mg, 3.87 mmol), triphenylphosphine (2.03 g, 7.75 mmol) and triethylamine (2.2 mL, 15.49 mmol) in dry THF (15 mL) at RT and stirred for 16 h. The resulting precipitate was filtered off and the filtrate evaporated. The residue was purified by SCX-2, eluting with MeOH followed by 2M NH3 in MeOH, to give the title compound as a buff-coloured foam (618 mg, 82%). LCMS (Method 1): Rt 1.55 min, m/z 195 [MH+].