Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:21])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11][CH3:12])=[N:6]2.C(Cl)Cl.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>>[Br:1][C:2]1[C:3]([Br:21])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11]([CH3:12])=[O:33])=[N:6]2
Reactant: COc1ccccc1-c1c(Br)c(Br)c2cnc(SC)nn12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccccc1-c1c(Br)c(Br)c2cnc(S(C)=O)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
Into a Round bottom flask, [A] 5,6-Dibromo-7-(2-methoxy-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.460 g, 0.00107 mol) and Methylene chloride (2 mL, 0.03 mol) were added. m-CPBA 70-75% (70:30, m-Chloroperbenzoic acid:3-Chlorobenzoic acid, 0.291 g, 0.00118 mol) was added portion wise over 20 minutes. The reaction was stirred at room temperature for one hour. The reaction was partitioned with DCM (200 mL) and saturated NaHCO3 (200 mL). The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give a yellow solid. The solid was washed with hexane to give 5,6-Dibromo-2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (0.465 g, 97%). NMR 1H (DSMO-d6)-9.27 (s, 1H), 7.50-7.62 (m, 2H), 7.40-7.48 (m, 2H), 3.80 (s, 3H), 2.90 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=[C:11]2[CH:21]([CH3:23])[CH3:22])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:24]([O:26][C:27]([CH:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:28])[CH3:25].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.CC1CCCO1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]([C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])([C:27]([O:26][CH2:24][CH3:25])=[O:28])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=[C:11]2[CH:21]([CH3:23])[CH3:22])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(O)CCCC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: CC1CCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCCCc2nc(C(C)C)n(Cc3ccc(Cl)c(Cl)c3)c21
Temperature: 25 °C

Procedure:
To a suspension of Intermediate 8 (270 mg) and triethylmethanetricarboxylate (0.324 ml) in toluene (4 ml) and methyltetrahydrofuran (4.00 ml), stirred at RT under an inert atmosphere of nitrogen, was added trimethylphosphine, 1M in toluene (1.529 ml). The resulting solution was cooled to −78° C. and diisopropyl azodicarboxylate (0.301 ml) was added dropwise via syringe and the reaction was stirred at −78° C. for 45 mins. The reaction mixture was removed from the cold bath and allowed to warm to RT and stirred under N2 atmosphere overnight. Reaction mixture concentrated slowly in vacuo using the rotavapor with the water bath at 50° C. The residue was taken up in DCM (20 ml) and washed with water (20 mL). The 2 phases were separated; the aqueous was extracted again with DCM (20 mL). The organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified by silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (435 mg).
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][CH2:22][C:21]4([CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:20]3=[O:29])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CO>C1COCC1.C(Cl)Cl.CCOC(C)=O>[OH:6][CH:7]1[CH2:8][CH2:9][CH:10]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:23][CH2:22][C:21]4([CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[C:20]3=[O:29])=[CH:17][CH:18]=2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: O=C1N(c2ccc(C3CCC(O)CC3)cc2)CCC12CCOCC2
Temperature: 60 °C
Yield: 100.7 %

Procedure:
Cis-2-{4-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-phenyl}-8-oxa-2-aza-spiro[4.5]decan-1-one (intermediate 19) (500 mg, 1.13 mmol) was dissolved in THF (10 mL). To this solution at rt was added TBAF (1 M in THF) (2.9 mL, 2.9 mmol, 2.5 equiv.). The reaction mixture was then heated to 60° C. (external) for 5 h. After the reaction was complete (TLC, 5% MeOH in DCM), the reaction was diluted with EtOAc (5 mL), quenched with NH4Cl (aq. saturated, 5 mL). The two layers were separated and the aq. layer was extracted with EtOAc (2×15 mL). The EtOAc solution was combined, washed with NH4Cl aq, NaHCO3 aq, and brine (10 mL each), sequentially, and dried over K2CO3, filtered and concentrated. The crude product was purified on a silica gel column, eluted with 5% MeOH in DCM to afford 0.375 g (100% yield) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:2].[Li]CCCC.CCCCCC.[C:29](=O)([O:33]CC)[O:30][CH2:31][CH3:32]>C1COCC1.O>[CH2:31]([O:30][C:29]([C:7]1[N:3]([CH2:1][CH3:2])[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[N:5][CH:6]=1)=[O:33])[CH3:32]
Reactant: CCOC(=O)OCC
Reactant: CCn1ccnc1-c1cccc2ccccc12
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1cnc(-c2cccc3ccccc23)n1CC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-ethyl-2-naphthalen-1-yl-1H-imidazole (1.11 g, 5 mmol) in anhydrous THF (30 ml) at −78° C. under nitrogen is added a solution of n-BuLi in hexane (1.6 M, 3.44 ml, 5.5 mmol, 1.1 eq.) dropwise. The resulting mixture is stirred at −78° C. for 1 hr, followed by the addition of diethyl carbonate (1.77 g, 15 mmol, 3.0 eq.). The resulting solution is stirred at −78° C. for 30 min, warmed to rt slowly, and stirred for an additional 30 min at rt. Water (30 ml) is added to quench the reaction, and THF is evaporated under reduced pressure. The residue is extracted with EtOAc (30 ml×2) and the combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. The crude product is purified through silica gel chromatography (hexanes/EtOAc, from 8:1 to 4:1) to give 3-ethyl-2-naphthalen-1-yl-3H-imidazole-4-carboxylic acid ethyl ester. LCMS 295 (M+1).
Reaction SMILES: O[CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([NH:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:4][C:3]1=2.[NH:16]1[CH:20]=[C:19]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[N:18]=[CH:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O>C1COCC1>[CH:24]([O:23][C:21]([C:19]1[N:18]([CH:2]2[C:3]3[C:8](=[CH:7][C:6]([NH:12][C:13](=[O:15])[CH3:14])=[CH:5][CH:4]=3)[CH2:9][CH2:10][CH2:11]2)[CH:17]=[N:16][CH:20]=1)=[O:22])([CH3:26])[CH3:25]
Reactant: CC(C)OC(=O)c1c[nH]cn1
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2O
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)CCCC2n1cncc1C(=O)OC(C)C
Reaction time: 0.25 h

Procedure:
To a suspension of N-(5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (0.553 g, 2.69 mmol) and isopropyl 4-imidazolecarboxylate (0.290 g, 1.88 mmol), which can be prepared as described in Example 1, in THF (10 mL) at 0° C. is added triphenylphosphine (1.415 g, 5.39 mmol) and dimethyl azodicarboxylate (40% wt. in toluene, 1.97 g, 5.39 mmol). The cooling bath is removed and the mixture is stirred for 15 min. Water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The resulting residue is purified by silica gel chromatography (elution with dichloromethane-methanol mixtures) to give 3-(6-acetylamino-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 342.2 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.39 (d, J=6.3 Hz, 3 H), 1.40 (d, J=6.0 Hz, 3 H), 1.71-1.82 (m, 1 H), 1.83-1.92 (m, 1 H), 2.16 (s, 3H), 2.17-2.30 (m, 2 H), 2.86 (ddd, J=16.9, 8.3; 5.6 Hz, 1 H), 3.00 (dt, J=16.9, 5.6 Hz, 1 H), 5.25 (sept., J=6.3 Hz, 1 H), 6.30 (t, J=5.3 Hz, 1 H), 6.93 (d, J=8.3 Hz, 1 H), 7.34-7.36 (m, 2 H), 7.53 (d, J=1.8 Hz, 1 H), 7.74 (d, J=1.0 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:10]=[C:11]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:14])[N:12]=1.CI.[CH3:31]CN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH:10]=[C:11]([C:13]([NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH3:31])[CH2:20][CH2:21]2)=[O:14])[N:12]=1
Reactant: CCN(CC)CC
Reactant: O=C(NC1CCNCC1)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Solvent: ClCCl
Solvent: CI
Product: CN1CCC(NC(=O)c2cn(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)n2)CC1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
To a solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(4-piperidinyl)-1H-imidazole-4-carboxamide (Example 37) (80 mg, 0.2 mmol) in CH2Cl2 (6 mL) was added CH3I (28.4 mg, 0.2 mmol) and Et3N (0.031 mL, 0.22 mmol). The reaction mixture was heated at reflux for 5 h, cooled to rt, and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (2M NH3 in methanol:EtOAc=1:10) to afford the product 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(1-methyl-4-piperidinyl)-1H-imidazole-4-carboxamide (24 mg, 28% yield): LC-MS m/z 429.1 (MH+), retention time 2.27 min (method 1); Rf=0.31 (EtOAc: 2M NH3 in MeOH=9:1).
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.N[C:21]1[C:25]([C:26]#[N:27])=C[NH:23][N:22]=1.C(CN(CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O.[OH-].[Na+]>O>[C:26]([C:25]1[CH:21]=[N:22][N:23]2[C:5]([C:7]3[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:19]=12)#[N:27]
Reactant: N#Cc1c[nH]nc1N
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(C(C)=O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2.0 gm N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl acetamide was added to a slurry of 40 ml water containing 0.83 gm of 3-amino-4-cyanopyrazole and 6.0 gm edetic acid. The reaction mass was heated to 60° C. for 3 hrs. After cooling the reaction mixture to 20° C., 15% aqueous sodium hydroxide solution was added and the pH of the reaction mixture was adjusted to between 9-10. The reaction mass was stirred for 1 hr. and filtered to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[CH3:22][C:23]1[C:27]2[CH:28]=[C:29]([NH2:32])[CH:30]=[CH:31][C:26]=2[O:25][N:24]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:32][C:29]2[CH:30]=[CH:31][C:26]3[O:25][N:24]=[C:23]([CH3:22])[C:27]=3[CH:28]=2)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(C)c(C)c1C(O)c1ccc(Cl)cc1
Reactant: Cc1noc2ccc(N)cc12
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(C)c(C)c1C(Nc1ccc2onc(C)c2c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.4 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (Step 28.2) and 3-methylbenzo[d]isoxazol-5-amine (Step 33.3). tR: 5.40 min (HPLC 1); tR: 1.20 min (LC-MS 2); ESI-MS: 439 [M+H]+ (LC-MS 2); Rf=0.77 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH2:10]([O:12][C:13](=[O:31])[C:14]([CH3:30])([CH3:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:31])[C:14]([CH3:30])([CH3:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[N:6]1[CH2:7][CH2:8][C:9]2[O:1][CH:2]=[CH:3][C:4]=2[CH2:5]1)[CH3:11]
Reactant: c1cc2c(o1)CCNC2
Reactant: CCOC(=O)C(C)(C)CCCCCC(Br)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2occc2C1
Temperature: 60 °C
Yield: 30.6 %

Procedure:
4,5,6,7-Tetrahydrofuro[3,2-c]pyridine (0.47 g, 3.82 mmol), 8-bromo-8-(2-chlorophenyl)-2,2-dimethyloctanoic acid ethyl ester (1.47 g, 3.78 mmol) in DMF (36 mL), and potassium carbonate (0.77 g, 5.58 mmol) were combined under an argon atmosphere at room temperature. The mixture was heated to 60° C. for 3 days under argon atmosphere, monitored by TLC. The DMF was evaporated under reduced pressure and the residue was dissolved in diethyl ether (120 mL), washed with water (3×30 mL), brine (30 mL), and dried over Na2SO4. The crude oil was purified by column chromatography (silica gel, ethyl acetate/heptane 1/9) to afford pure 8-(2-chlorophenyl)-8-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid ethyl ester (Compound Ip, 0.50 g, 30.3% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 7.48 (d, 1H, J=7.5 Hz), 7.36 (d, 1H, J=7.8 Hz), 7.32-7.15 (m, 3H), 6.17 (s, 1H), 4.20 (dd, 1H, J=9.0, 4.8 Hz), 4.08 (q, 2H, J=7.2 Hz), 3.62 (d, 1H, J=13.5 Hz), 3.11 (d, 1H, J=13.5 Hz), 2.88-2.58 (m, 4H), 1.95-1.70 (m, 2H), 1.45-1.40 (m, 2H), 1.30-1.0 (m, 15H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 178.01, 149.01, 140.94, 139.50, 135.00, 129.57, 129.04, 128.03, 126.85, 115.92, 108.90, 63.43, 60.36, 47.65, 47.54, 42.36, 40.91, 33.27, 30.57, 25.67, 25.41, 25.06, 24.73, 14.55. HRMS (HR, DART-TOF): Calculated for (M+H)+: 432.2300, found 432.2316.
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[CH3:11][C:12]1[N:17]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:15]=[CH:14][CH:13]=1>CCCCCC.O1CCCC1.[Cl-].[Cl-].[Zn+2]>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:11])[N:17]=1
Reactant: c1ccoc1
Reactant: Cc1cccc(OS(=O)(=O)C(F)(F)F)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccc(-c2ccco2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
40 ml of a 1.6 M solution of n-butyllithium in hexane are introduced dropwise into a solution of 4.36 ml of furan (60 mmol) and 40 ml of tetrahydrofuran cooled to 0° C. The solution is stirred for 3 hours at 0° C. and then it is cooled to -40° C. before introducing 120 ml of a 0.5 M solution of zinc dichloride in tetrahydrofuran. The mixture is stirred for 2 hours at room temperature and then the reaction mixture is added to a solution of 9.17 g of trifluoromethanesulfonic acid 6-methylpyridin-2-yl ester (40 mmol) in 20 ml of tetrahydrofuran containing 2.30 g of tetrakis-(triphenylphosphine)palladium (2 mmol). The reaction mixture is maintained under reflux for 2 hours under nitrogen and then cooled and extracted with 1N HCl. The acidic aqueous phase is neutralized with 10N NaOH and then extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and the solvent evaporated off. The expected product is isolated by rectification under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11](/[CH:21]=[CH:22]/[C:23]([O:25]C)=[O:24])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/c1cnc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)/C=C/c1cnc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of (E)-methyl 3-(5,6-bis(4-fluorophenyl)pyrazin-2-yl)acrylate (120 mg, 0.34 mmol, 1.00 equiv) in methanol (15 mL) was added a solution of sodium hydroxide (136 mg, 3.40 mmol, 9.97 equiv) in water (2 mL). The resulting solution was stirred for 2 h at 50° C. in an oil bath, concentrated in vacuo, and diluted with 20 mL of water. The pH value was adjusted to 4-5 with HCl (1M). The resulting solids were collected by filtration, and purified by Prep-HPLC with the following conditions (1#-Waters 2767-2): Column, SunFire Prep C18, 19*150 mm Sum; mobile phase, water with 0.05% TFA and CH3CN (50% CH3CN up to 60% in 8 min, hold 60% in 1 min, up to 100% in 0.1 min, hold 100% in 0.9 min); Detector, UV 220&254 nm. This resulted in 50 mg (43%) of (E)-3-(5,6-bis(4-fluorophenyl)pyrazin-2-yl)acrylic acid as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.C([O:18][B:19](OCCCC)[O:20]CCCC)CCC>C(OCC)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:20])[OH:18])=[CH:3][CH:4]=1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: Cc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccc(B(O)O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
To a solution of 4-iodotoluene (35 g, 160.5 mmol) in diethyl ether (400 mL) was added n-butyllithium (2 M in pentane, 88.3 mL, 176.6 mmol) at 0° C. After stirring at 0° C. for another 15 min the solution was cooled to −60° C. and tributylborate (60.6 mL, 224.7 mmol) was added. The cooling bath was removed and the reaction allowed to heat up to room temperature. The solution was acidified with hydrochloric acid (2 N, 280 mL) and the organic phase separated off. The aqueous phase was extracted with diethyl ether 2×125 mL). The combined organic phases were extracted with sodium hydroxide (1 N, 5×50 mL). The combined aqueous extracts were acidified to give 18.6 g of the desired material.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:47][C:48]1[C:49]([CH3:55])=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:51][C:50]4[CH:52]=[CH:53][CH:54]=[C:48]([Cl:47])[C:49]=4[CH3:55])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1c(N)cccc1Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2cccc(Cl)c2C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-chloro-2-methylaniline (Aldrich) to give the title product. LC-MS (ES+) 788 [(M+H)+].
Reaction SMILES: O[C:2]1[CH:16]=[C:15]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:20]>CN(C=O)C>[CH3:20][NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][C:8]1[C:15]2[C:5](=[CH:4][CH:3]=[CH:2][CH:16]=2)[NH:6][CH:7]=1
Reactant: CI
Reactant: N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 0.5 h

Procedure:
The protected tryptophan derivative from above (0.573 g, 1.00 mmol) was dissolved in DMF (3 mL) and the solution cooled in ice. Sodium hydride (60% oil dispersion, 0.048 g, 1. 2mmol) was added and the mixture stirred for 30 min. Iodomethane (0.093 mL, 1.5 mmol) was added and stirring continued for an additional hour. The reaction was then quenched with 10% citric acid (2 mL) and water (25 mL), and extracted with Et2O (100 mL). The extract was dried (MgSO4) and concentrated, and the residue purified by flash chromatography (20-30% EtOAc 1 hexane as eluent) to give the desired N-methyltryptophan derivative (0.284 g).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH:12][CH2:13][C:14]1([C:17]#[N:18])[CH2:16][CH2:15]1.CCN(CC)CC>ClCCl>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:12][CH2:13][C:14]2([C:17]#[N:18])[CH2:16][CH2:15]2)(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: N#CC1(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C#N)CC2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
TsCl (7.25 g, 38 mmol) was added in one portion to a stirred solution of 1-(hydroxymethyl)cyclopropanecarbonitrile (3.1 h, 32 mmol) in dichloromethane (75 mL) at 0° C. Et3N (4.1 g, 40 mmol) was added. The reaction mixture was stirred at rt over night. The mixture was diluted with dichloromethane, washed with water, 0.5 N NaOH, brine. The organic extract was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to give 18A (6.43 g, 81% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:10][C@H:11]([CH2:19][C:20]1[N:21]=[N:22][N:23]([CH2:25][CH2:26]O)[CH:24]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:42]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O.F.F.F.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:10][C@H:11]([CH2:19][C:20]1[N:21]=[N:22][N:23]([CH2:25][CH2:26][F:42])[CH:24]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1cn(CCO)nn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1cn(CCF)nn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 144 h

Procedure:
Di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-{[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]methyl}-L-glutamate (74 mg, 152.7 μmol) was dissolved in tetrahydrofuran (5 ml) and triethyl amine (319 μl, 2.3 mmol), Nonafluorobutanesulfonyl fluoride (185 mg, 611 μmol), and Triethylamine trihydrofluoride (98 mg, 611 mmol) were added subsequently. The mixture was stirred at room temperature for 6 days. The mixture was than concentrated in vacuo, and the residue was purified by silica gel chromatography to yield 30 mg (40%) of slightly impure product, which was used in the following step.