Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1CCNCC1
Reactant: C[C@H](CI)CN1C(=O)CSc2ccccc21
Solvent: CC#N
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)CSc3ccccc32)CC1
Temperature: 60 °C
Reaction time: 72 h
Yield: 74.8 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one (108LM37-34) (0.105 g, 0.304 mmol) and 4-butyl-piperidine (0.052 g, 0.369 mmol) in MeCN (½ mL) were reacted according to GP10 shaking at 60° C. for 3 days. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:20) to give the title compound (108LM43-40) (0.082 g, 75%). 1H NMR (CDCl3) δ 7.34 (d, J=9.1 Hz, 1H), 7.25-7.17 (m, 2H), 7.02-6.95 (m, 1H), 4.15-3.99 (m, 2H), 3.35 (s, CH2), 2.83 (bd, J=10.4 Hz, 1H), 2.68 (bd, J=10.4 Hz, 1H), 2.20-2.05 (m, 2H), 2.00-1.85 (m, 2H), 1.82-1.73 (m, 1H), 1.67-1.55 (m, 2H), 1.30-1.14 (m, 9H), 0.88 (t, J=7.2, CH3), 0.82 (d, J=6.5 Hz, CH3); 13C NMR (CDCl3) δ 166.0, 139.2, 128.8, 127.1, 124.8, 123.5, 118.9, 63.8, 55.5, 54.4, 47.7, 36.6, 36.1, 32.9, 32.8, 32.1, 29.4, 29.3, 23.2, 16.7, 14.4; HPLC-MS (ammonium acetate) [M+H]+=361.3.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:14]=3[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:30](=[O:35])(OCC)[NH2:31].C(O)C>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[C:1]12([CH2:11][N:12]3[C:13]4[C:14](=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:31][C:30]3=[O:35])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CCOC(N)=O
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1NCC12CC3CC(CC(C3)C1)C2
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1CC12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
A mixture of 3.9 g of 2-(1-adamantylmethyl-amino)-5-nitrobenzophenone, 6.4 g of ethyl carbamate and 0.45 g of anhydrous zinc chloride was heated at 170°- 180°C for 1 hour, and then, distillating off the produced ethanol, heating was continued at that temperature for additional 1 hour. After cooling, chloroform was added thereto and insoluble material was filtered off. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residual oil was chromatographed on silica gel using chloroform as eluting solvent to give 1-(1-adamantylmethyl)-4-phenyl-6-nitro-2(1H)-quinazolinone, m.p. 230°- 233°C, following recrystallization from a mixture of ethanol and chloroform.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][C@H:22]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])[CH2:21]2)[C:3]=1[C:4]([O:6]CC1C=CC=CC=1)=[O:5].[H][H]>C1COCC1.[Pd]>[CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][C@H:22]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)[O:31][C:32]=3[CH3:33])[CH2:21]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(-c2nc(CO[C@H]3CCC[C@@H](OCc4cccc(C)c4C(=O)OCc4ccccc4)C3)c(C)o2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(CO[C@H]3CCC[C@@H](OCc4cccc(C)c4C(=O)O)C3)c(C)o2)cc1
Yield: 42 %

Procedure:
from benzyl methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-cyclohexyloxymethyl]benzoate: 15 g (27.8 mmol) of benzyl methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]benzoate are dissolved in 300 ml of THF. 700 mg of palladium on carbon (5%) are added. Subsequently, hydrogenation is effected at standard pressure and RT until no more hydrogen is taken up. The reaction mixture is filtered and the organic phase is subsequently concentrated fully under reduced pressure. The residue is taken up in 150 ml of tert-butyl methyl ether, 150 ml of water and 150 ml of saturated sodium hydrogencarbonate solution. After phase separation, the aqueous phase is washed with 150 ml of tert-butyl methyl ether. Subsequently, 150 ml of diisopropyl ether are added and the mixture is acidified with concentrated hydrochloric acid. After phase separation, the organic phase is washed four times with 100 ml each time of water and then concentrated fully under reduced pressure. The residue is stirred with a little diisopropyl ether. The solid is filtered and dried under reduced pressure. 2-methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl-oxymethyl]benzoic acid is obtained in 42% yield as a crystalline solid.
Reaction SMILES: CO[C:3](=[O:32])[C@H:4]([CH2:28][CH2:29][S:30][CH3:31])[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH3:33]>CO>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([NH2:33])=[O:32])[CH2:28][CH2:29][S:30][CH3:31])=[O:27])=[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:9]=2)[CH:16]=1
Reactant: N
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1
Solvent: CO
Product: CSCC[C@H](NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1)C(N)=O
Temperature: 0 °C

Procedure:
[4-(3-pyridylmethylamino)-2-phenylbenzoyl]methionine methyl ester (80 mg, 0.18 mmol), prepared as in Example 192C, was dissolved in methanol (5 mL), cooled to 0° C., and the solution was saturated with anhydrous ammonia. The reaction was sealed for 72 hours at ambient temperature. Evaporation to dryness afforded [4-(3-pyridylmethylamino)-2-phenylbenzoyl]methionineamide (78 mg). MS m/e 435 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.59 (m, 2H), 1.83 (m, 2H), 2.02 (s, 3H), 4.43 (s, 2H), 4.51 (m, 1H), 5.16 (s, 1H), 5.64 (m, 1H), 6.14 (m, 1H), 6.50 (d, J=3 Hz, 1H), 6.63 (m, 1H), 7.38 (m, 7H), 7.66 (m, 2H), 8.55 (m, 1H), 8.62 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: COC(=O)CCCC(CCCN)CCc1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCC(CCCNS(=O)(=O)c1ccc(Cl)cc1)CCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.127 g (9.045 mmol) of methyl 8-amino-5-[2-(3-pyridyl)ethyl]-octanoate in 5 mL methylene chloride are added a few crystals of 4-dimethylaminopyridine followed by 0.1 mL (0.7 mmol) triethylamine and 0.112 g p-chlorophenylsulfonyl chloride, and the solution is stirred at room temperature for 16 hours. The reaction is diluted with 10 mL methylene chloride and washed with saturated aqueous sodium bicarbonate solution. The organic phase is dried (MgSO4), filtered and evaporated to obtain an oil which is purified by preparative thin layer chromatography to give methyl 8-(p-chlorophenylsulfonamido)-5-[2-(3-pyridyl)ethyl]-octanoate as an oil.
Reaction SMILES: Cl.CCO.C(OC([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH:22]=[C:21]([C:23]3[CH:32]=[N:31][C:30]4[C:25](=[C:26]([Br:33])[CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH:20]=[N:19]2)[CH2:14][CH2:13]1)=O)(C)(C)C>>[Br:33][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[N:24]=[C:23]([C:21]1[CH:20]=[N:19][N:18]([CH:15]3[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]3)[CH:22]=1)[CH:32]=[N:31]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4cccc(Br)c4n3)cn2)CC1
Agent: Cl
Solvent: CCO
Product: Brc1cccc2ncc(-c3cnn(C4CCNCC4)c3)nc12
Temperature: 50 °C

Procedure:
A 1.2 M solution of HCl in EtOH (60 ml, 72 mmol) is added to 4-[4-(8-Bromo-quinoxalin-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Step 94.1, 1.98 g, 4.32 mmol) and the reaction mixture is heated at 50° C. for 12 h. After cooling, the yellow suspension is concentrated under vacuo and the residue is diluted with CH2Cl2, poured onto a saturated solution of NaHCO3 and extracted 3× with CH2Cl2. The combined organic layers are washed with water, brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is used without further purification in the next step, and afford the title compound as pale orange solid, Rt=0.802 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 358 (M+1, 79Br)+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:13])OCC)[CH:5]=[CH:4][C:3]=1[Cl:14].[CH3:15][NH:16][CH3:17]>C(O)C>[CH3:15][N:16]([CH3:17])[C:9]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([Cl:14])=[C:2]([NH2:1])[N:7]=1)=[O:13]
Reactant: CCOC(=O)Nc1ccc(Cl)c(N)n1
Reactant: CNC
Solvent: CCO
Product: CN(C)C(=O)Nc1ccc(Cl)c(N)n1

Procedure:
A mixture of ethyl N-(6-amino-5-chloro-2-pyridyl)carbamate (64.7 g., 0.3 mole), dimethylamine (45 g., 1.0 mole) and 300 ml. of ethanol is heated at 120° C. for 24 hours in a pressure vessel. The reaction mixture is then concentrated in vacuo and 68 g. of brown solid is obtained. Recrystallization from n-butyl chloride gives pure material, m.p. 139°-141°
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]([Cl:16])([Cl:15])[C:10]([N:12]=[C:13]=[O:14])=[O:11]>O.CC(C)=O>[Cl:8][C:9]([Cl:16])([Cl:15])[C:10]([NH:12][C:13](=[O:14])[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11]
Reactant: Oc1ccccc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC(=O)C(Cl)(Cl)Cl)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.7 g (0.05 mol) of phenol are dissolved in a mixture of 10 g of water and 10 g of acetone. 9.4 g (0.05 mol) of trichloroacetyl isocyanate are subsequently added dropwise over the course of 30 minutes. The mixture is stirred at room temperature for 30 minutes and under reflux for 2.5 hours. The solvent mixture is evaporated in a rotary evaporator, and the solid obtained is recrystallized from DMSO (dimethyl sulfoxide).
Reaction SMILES: [C:1]([CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:4][C:5](=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)#[N:2].[NH4+].[Cl-].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]([NH:4][CH:3]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:1]2[NH:27][N:26]=[N:25][N:2]=2)=[O:16])=[CH:8][CH:9]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1ccc(CC(=O)NC(C#N)c2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CC(=O)NC(c2ccccc2)c2nnn[nH]2)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
To a solution N-[cyano(phenyl)methyl]-2-(4-isopropylphenyl)acetamide (58.0 mg, 0.198 mmol) in 0.5 ml of anhydrous DMF was added NH4Cl (12.0 mg, 0.218 mmol) and NaN3 (14.00 mg, 0.218 mmol). The resulting solution was stirred at 110° C. for 16 hour. Filtered and the filtrate was purified by preparative HPLC (5-90% CH3CN/H2O over 30 min, 0.05% added TFA, C18 column) to afford 53.0 mg (80%) of the title compound. 1H NMR (CD3OD, 400 MHz) δ 7.326 (m, 5H), 7.169 (ABq, J=8.2 Hz, 4H), 6.460 (s, 1H), 3.583 (ABq, J=14.5 Hz, 2H), 2.856 (sept, J=7.0 Hz, 1H), 1.214 (d, J=7.0 Hz, 6H). ES-MS [M+1]+: 336.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23]Br)[CH:7]=1)[CH3:2].[F:26][C:27]([F:31])([F:30])[CH2:28][SH:29]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23][S:29][CH2:28][C:27]([F:31])([F:30])[F:26])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Reactant: FC(F)(F)CS
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1

Procedure:
As described for Example 21, [3-(2-bromomethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester and 2,2,2-trifluoroethanethiol were reacted to provide {4-chloro-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester, which was reduced to the amine and then treated with pivaloyl chloride to provide {4-chloro-3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided the acid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[N:18]=[C:19]([NH:33][C:34](=[O:38])[O:35][CH2:36][CH3:37])[S:20][C:21]=2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[N:18]=[C:19]([NH:33][C:34](=[O:38])[O:35][CH2:36][CH3:37])[S:20][C:21]=2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Nc1nc(CCc2ccc(N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.3 %

Procedure:
Ethyl {4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}carbamate (140 mg) and 4N HCl in 1,4-dioxane solution (3 ml) were combined under N2 atmosphere. The reaction mixture was stirred at r.t. for 2 hours. The solvent was removed in vacuo. The residue was dissolved in water and AcOEt. The mixture was made basic (pH=8) by 1N—NaOH. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo to give ethyl {4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}carbamate (125.6 mg) as an off-white amorphous substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](B(O)O)[CH:29]=2)[NH:24][N:23]=1>>[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])[CH:29]=2)[NH:24][N:23]=1
Reactant: Cc1n[nH]c2ccc(B(O)O)cc12
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4[nH]nc(C)c4c3)ccn2c1=O
Yield: 91.1 %

Procedure:
Methyl 8-(3-methyl-1H-indazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A′ from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and (3-methyl-1H-indazol-5-yl)boronic acid (176.1 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (120 mg, 88%).
Reaction SMILES: [CH2:1]([N:8]([CH3:24])[C@H:9]([C:21]([OH:23])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:67][C:68]1[CH:77]=[CH:76][C:75]2[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=2)[CH:69]=1>C(OCC)(=O)C.O1CCCC1>[CH:69]1[C:70]2[C:75](=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH:76]=[CH:77][C:68]=1[NH:67][C:21](=[O:23])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:24]
Reactant: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc2ccccc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Nc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A mixture of Nα-benzyl-Nδ-Boc-Nα-methylornithine (2.13 g, 6.3 mmol), diisopropyl-ethylamine (2.2 ml, 12.6 mmol), and anhydrous tetrahydrofuran (20 ml) was treated with PyBop (4 g, 7.6 mmol) at 0° C. for 10 min., followed by the addition of β-amino-naphthalene (1.09 g, 7.6 mmol). The resulting solution was stirred at ambient temperature overnight, and the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (hexane/ethyl acetate) to afford Nα-benzyl-Nδ-Boc-Nα-methylornithine 2-naphthyl-amide (2 g): 1H NMR (400 MHz, CDCl3) δ1.43 (s, 9H), 1.6-1.9 (m, 4H), 2.38 (s, 3H), 3.2-3.3 (m, 2H), 3.7-3.8 (m, 2H), 4.7 (s, 1H), 7.25-7.8 (m, 11H), and 8.25 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[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:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([CH2:46][C:47]([NH2:49])=[O:48])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][C:47]([NH2:49])=[O:48])[CH2:41][CH2:42]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:35][CH2:36][CH3:37])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NC(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound. HR-MS (ES, m/z) calculated for C36H44N5O3Cl2 [(M+H)+] 664.2816, observed 664.2810.
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C=CC(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[O:26][C:27]([CH3:55])=[C:28]([CH2:30][O:31][C:32]2[CH:52]=[CH:51][C:35]([CH2:36][O:37][C:38]3[C:42]([CH:43]=O)=[CH:41][N:40]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:39]=3)=[CH:34][C:33]=2[O:53][CH3:54])[N:29]=1.O1CCCC1>C(COC)OC.O.CO>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[O:26][C:27]([CH3:55])=[C:28]([CH2:30][O:31][C:32]2[CH:52]=[CH:51][C:35]([CH2:36][O:37][C:38]3[C:42]([CH2:43][C:16]#[N:17])=[CH:41][N:40]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[N:39]=3)=[CH:34][C:33]=2[O:53][CH3:54])[N:29]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2CC#N)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a mixture of potassium tert-butoxide (0.94 g) and dimethoxyethane (30 mL) was added p-toluenesulfonyl methylisocyanide (0.86 g) at −78° C., and a solution of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (1.96 g) in dimethoxyethane (50 mL)-tetrahydrofuran (10 mL) was added at −78° C. After stirring at the same temperature for 1 hr, the reaction mixture was heated to room temperature. Methanol (30 mL) was added to the obtained mixture, and the mixture was heated under reflux for 1 hr. After cooling, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}acetonitrile as colorless crystals (1.21 g, yield 61%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 153-154° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=2[OH:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.Cl[C:48]1[C:53]([CH3:54])=[CH:52][C:51]([N+:55]([O-:57])=[O:56])=[CH:50][C:49]=1[CH3:58].Cl>CN1CCCC1=O>[CH3:54][C:53]1[CH:52]=[C:51]([N+:55]([O-:57])=[O:56])[CH:50]=[C:49]([CH3:58])[C:48]=1[O:17][C:15]1[CH:14]=[CH:13][C:12]([OH:18])=[C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:16]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: O=S(=O)(c1ccc(F)cc1)c1cc(O)ccc1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A solution of 2-(4-fluoro-benzenesulfonyl)-benzene-1,4-diol (10.0 g, 37.3 mmol) in dry 1-methyl-2-pyrrolidinone (100 mL) with 3 Å molecular sieves (3.0 g) was sparged with dry nitrogen for 15 min at RT. The solution was cooled to 0° C. and potassium bis(trimethylsilyl)amide (18.59 g, 93.2 mmol) was added in a single portion to give a deep red suspension. The suspension was warmed to RT with continued sparging. 18-Crown-6 (10.8 g, 41.0 mmol) was added in a single portion and the solution was cooled to 0° C. To the cooled suspension was added 2-chloro-1,3-dimethyl-5-nitro-benzene (8.30 g, 44.7 mmol) to give a brown solution and sparging was ceased. The solution warmed to RT and stirred under dry nitrogen for 3 h. The crude reaction mixture was poured into 1M HCl (1 L) at 0° C. and extracted with EtOAc (3×300 mL). Combined extracts were washed with 1 M HCl (4×1 L) and brine (1 L), dried over anhydrous sodium sulfate, treated with activated carbon and filtered. The filtrate was concentrated to a tan solid which was filtered through silica gel (150 g) with 1:9:10 methanol:hexanes:CH2Cl2 (1.5 L). Concentration of the filtrate gave the title compound of Step C as a tan solid (11.4 g). The title product of Step C was used in the next step without further purification. MS (APCI−) Calc.: 417.1, Found: 416.0 (M−1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:32])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:31])[CH:18]=2)[CH:13]=1.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34].C(N(CC)CC)C>ClCCl>[CH3:8][O:9][C:10](=[O:32])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH2:27][CH2:26]2)=[O:24])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:31])[CH:18]=2)[CH:13]=1
Reactant: CCS(=O)(=O)Cl
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)N2CCNCC2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(C(=O)c2c(C)c(CC(=O)OC)cc3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of [6-fluoro-3-methyl-4-(piperazine-1-carbonyl)-naphthalen-2-yl]-acetic acid methyl ester trifluoroacetate (45.8 mg, 0.10 mmol) and ethanesulfonyl chloride (14 μL, 0.15 mmol) in dichloromethane was added triethylamine (306 μL, 2.2 mmol). The resulting mixture was stirred at room temperature overnight, and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 20-40% ethyl acetate in petroleum ether) to afford [4-(4-ethanesulfonyl-piperazine-1-carbonyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (38 mg, 87%) as a white solid.