Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([C:11](=[O:21])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])[C:5]2=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.O.Cl>CN1C(=O)CCC1>[F:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:11]([C:10]1[C:5]2[C:6](=[N:7][C:2]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:3][CH:4]=2)[NH:8][CH:9]=1)=[O:21]
Reactant: O=C(Cc1cccc(F)c1F)c1c[nH]c2nc(Cl)ccc12
Reactant: C1CCNC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Cc1cccc(F)c1F)c1c[nH]c2nc(N3CCCC3)ccc12

Procedure:
A solution of 1-(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(2,3-difluoro-phenyl)-ethanone (100 mg, 0.29 mmol) and pyrrolidine (1 mL) in NMP (2 mL) was heated in a sealed tube with microwave at 220° C. for 15 min. The solution was poured into water and 0.5N HCl was added to precipitate the product. The crude product was collected by filtration, washed with water, and dried on the pump for direct use (80 mg, 0.23 mmol, 79%). MS (ES+): m/e=342.2 (M+H); LC: 2.92 min.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:50][C:51](=[O:54])[CH:52]=[CH2:53]>CC([O-])=O.CC([O-])=O.[Pd+2].O>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2](/[CH:53]=[CH:52]/[C:51](=[O:54])[CH3:50])=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: C=CC(C)=O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Product: CC(=O)/C=C/c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.2, 250 mg, 0.560 mmol), Pd(OAc)2 (3.77 mg, 0.017 mmol), tri-o-tolylphosphine (20.46 mg, 0.067 mmol), but-3-en-2-one (55.1 μL, 0.672 mmol) and TEA (102 μL, 0.728 mmol) were added to a MW vial, which was sealed and purged with argon. DMF (1.87 mL) was added and the RM was stirred at 130° C. for 6 h. Additional but-3-en-2-one (22.96 μL, 0.280 mmol) was then added and mixture was stirred at 130° C. for 16 h. The RM was poured into water (25 mL) and extracted with DCM (3×20 mL). The combined extracts were dried over MgSO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1) from 40% to 75% EtOAc-EtOH+0.1% NH4OH (9:1)). Fractions containing pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was azeotroped with xylene and triturated in cyclohexane to yield the title compound as a yellow solid. UPLC-MS (Condition 1) tR=2.39 min, m/z=436.0 [M+H]+, m/z=434.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.91 (m, 1H) 1.91-2.00 (m, 1H) 2.35 (s, 3H) 3.43 (d, J=11.25 Hz, 1H) 3.59-3.67 (m, 1H) 3.78-3.88 (m, 2H) 4.34 (br. s, 1H) 4.99 (d, J=3.18 Hz, 1H) 6.61 (d, J=15.89 Hz, 1H) 7.36 (d, J=8.31 Hz, 2H) 7.81-7.93 (m, J=16.14, 9.29 Hz, 3H) 8.29 (d, J=2.20 Hz, 1H) 8.71 (d, J=2.45 Hz, 1H) 10.21 (s, 1H).
Reaction SMILES: C([Li])C1C=CC=CC=1.[CH2:9]([C:16]1[C:25](Cl)=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C-:27]#[N:28]>>[CH2:9]([C:16]1[C:25]([C:27]#[N:28])=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1nc2ccccc2nc1Cc1ccccc1
Reactant: [C-]#N
Agent: [Li]Cc1ccccc1
Product: N#Cc1nc2ccccc2nc1Cc1ccccc1

Procedure:
Intermediate 3 can be prepared from the starting material 2,3-dichloroquinoxaline 1 following the reaction in Scheme 1. In this manner, quinoxaline 1 can be reacted with benzylmagnesium chloride in THF to afford 2-benzyl-3-chloroquinoxaline 2. 2-Benzylquinoxalines can also be prepared by reaction with alternative alkylating reagents, such as, but not limited to, benzyllithium. 2-Benzyl-3-chloroquinoxaline 2 can be reacted with cyanide to obtain intermediate 2-benzyl-3-cyanoquinoxaline 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:24])[C:21](O)=[S:22])=[CH:15][CH:14]=3)[N:8]([CH3:25])[C:7]=2[CH:26]=1.O1CCCC1.ClC(OCC)=O.[NH3:38]>C(N(CC)CC)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH:20]([CH3:24])[C:21]([NH2:38])=[S:22])=[CH:17][CH:18]=3)[N:8]([CH3:25])[C:7]=2[CH:26]=1
Reactant: N
Reactant: COc1ccc2nc(COc3ccc(CC(C)C(O)=S)cc3)n(C)c2c1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2nc(COc3ccc(CC(C)C(N)=S)cc3)n(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid (1.1 g), tetrahydrofuran (15 ml) and dimethylformamide (15 ml) were added successively triethylamine (0.82 ml) and ethyl chloroformate (0.28 ml). The mixture was stirred at room temperature for 30 minutes. After addition of aqueous ammonia solution (5 ml, 28%) the mixture was stirred at room temperature for 15 minutes and allowed to stand overnight. The solvent of the reaction mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate and then recrystallized from a mixture of ethanol and ethyl acetate to afford the title compound (0.45 g, mp 204-206° C.).
Reaction SMILES: I.C[O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[ClH:23]>>[ClH:23].[CH:17]1([N:14]2[CH2:13][CH2:12][CH:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:22])=[O:3])=[CH:10][CH:9]=3)[CH2:16][CH2:15]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1ccc(C2CCN(C3CCCC3)CC2)cc1
Agent: Cl
Agent: I
Product: O=C(O)c1ccc(C2CCN(C3CCCC3)CC2)cc1

Procedure:
4-(1-Cyclopentyl-piperidin-4-yl)-benzoic acid methyl ester hydroiodide (1.06 mmol) is dissolved in 4N HCl (5 ml) and heated under reflux for 10 hours. After cooling the solvent is evaporated and the residue is suspended in acetone and the solid filtered of, washed with acetone and dried (vacuum). A grey-brown powder with mp. >270° C. is obtained.
Reaction SMILES: CO[C:3](=[O:26])[CH:4]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[CH3:27][NH:28][C:29]([NH2:31])=[O:30].C[O-].[Mg+2].C[O-].CO>>[Cl:25][C:20]1[CH:19]=[C:18]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH:7]2[O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:3]([NH:31][C:29]([NH:28][CH3:27])=[O:30])=[O:26])[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: COC(=O)C(CC1CCCC1OC1CCCCO1)c1ccc(Cl)c(Cl)c1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1OC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Yield: 11.8 %

Procedure:
2-(3,4-Dichloro-phenyl)-3-[2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (400 mg, 0.99 mmol) and methylurea (110.7 mg, 1.49 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. % , 2.85 mL, 1.99 mmol) was heated under reflux at 110° C. for 6 h. The reaction mixture was then concentrated in vacuo and filtered through a plug of celite (ethyl acetate as eluent). Flash chromatography (Merck Silica gel 60, 230-400 mesh, 100% ethyl acetate) afforded 1-{2-(3,4-dichloro-phenyl)-3-[2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionyl}-3-methyl-urea (52 mg, 11.8%) as a white solid: mp 68-70° C.; FAB-HRMS m/e calcd for C21H28Cl2N2O4 (M+H)+ 443.1504. found 443.1499.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[CH2:2]1.Cl[C:10]1[N:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=1>C(O)(C)C>[NH2:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[CH2:2]2)[N:15]=1
Reactant: O=C(O)C1CCNC1
Reactant: Nc1ccnc(Cl)n1
Solvent: CC(C)O
Product: Nc1ccnc(N2CCC(C(=O)O)C2)n1
Temperature: 80 °C
Yield: 67.2 %

Procedure:
A 100 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with pyrrolidine-3-carboxylic acid (1.20 g, 10 mmol), 2-chloropyrimidin-4-amine (1.30 g, 10 mmol), isopropyl alcohol (IPA, 40 mL), and TEA (6 mL). The mixture was heated at 80° C. overnight (O/N). After this time the reaction was cooled to room temperature (r.t.). It was then filtered and the filter cake was washed with DCM to afford 102a (1.4 g, 67%) as a pale yellow solid. MS: [M+H]+ 209.1
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[C:11]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:20][CH:19]=3)[CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1)C.O.[OH-].[Li+].CCOC(C)=O.Cl>C1COCC1.O>[F:31][C:27]1[C:28]([F:30])=[CH:29][C:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:10]=3[CH:9]=[N:8][N:7]4[CH2:6][CH2:5][C:4]([OH:34])=[O:3])=[CH:23][CH:22]=2)=[C:25]([O:32][CH3:33])[CH:26]=1
Reactant: CCOC(=O)CCn1ncc2c(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2cnn3CCC(=O)O)cc1
Yield: 59.3 %

Procedure:
3-[4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-propionic acid ethyl ester (0.095 g, 0.204 mmol) and lithium hydroxide hydrate (10 mg, 0.245 mmol) in 5 mL THF/1 mL H2O was stirred at RT for 3 hrs. The reaction was distributed between EtOAc and H2O. The water layer was made acidic to pH 3 with 1N HCl and the organic layer was separated and concentrated in vacuo. The crude product was purified by flash chromatography with a gradient from 0-3% methanol in CH2Cl2 to yield 3-[4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-propionic acid as a white solid (53 mg, 59%). LC-MS (ES) calculated for C24H20F2N2O04, 438.43; found m/z 439 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:11][CH:10]=2)[N:6]([C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:5]=1)([CH3:3])=[CH2:2]>C1COCC1.CO.[Pd]>[CH:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:11][CH:10]=2)[N:6]([C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(-c2ccc(OCCNS(C)(=O)=O)cc2)n(-c2ccc(OC)nc2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-n2nc(C(C)C)cc2-c2ccc(OCCNS(C)(=O)=O)cc2)cn1
Yield: 57.9 %

Procedure:
A mixture of 10% Pd-C 50% wet (20 mg) and N-(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide (118 mg) in THF (1 ml) and MeOH (1 ml) was hydrogenated under H2 1atm at ambient temperature for 1 day. The catalyst was removed by filtration. The filtrate and combined washings were concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by AcOEt/n-hexane=70%. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residue was recrystallized from AcOEt-IPE to give N-(2-{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide (68.6 mg) as white powder.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Li])CCC.CCCCCC.[O:35]1[C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=[N:36]1.O>O1CCCC1>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:2]=1[C:40]([C:39]1[O:35][N:36]=[CH:37][CH:38]=1)=[O:41]
Reactant: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Reactant: O=C(Cl)c1ccno1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccno3)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) was dissolved in tetrahydrofuran (6 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) was added to the solution, and the mixture was stirred at −78° C. for 20 min. Isoxazole-5-carbonyl chloride (0.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (27 mg, yield 26%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=2[N:7]([C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][CH:5]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Br[CH2:31][C:32]([C:34]1[O:35][CH:36]=[CH:37][CH:38]=1)=[O:33]>O1CCCC1>[O:35]1[CH:36]=[CH:37][CH:38]=[C:34]1[C:32]([CH2:31][N:10]1[C:9]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=2[N:7]([C:16](=[O:21])[C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:6][CH:5]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:4]1=[O:3])=[O:33]
Reactant: O=C(CBr)c1ccco1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccco1)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
60% Sodium hydride (320 mg) was suspended in tetrahydrofuran (30 ml), under ice-cooling 2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Step I of Example 89, and the mixture was stirred for 30 minutes. Bromomethyl(furan-2-yl)ketone (1.89 g) was added dropwise thereto, stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, water (100 ml) and ethyl acetate (100 ml) were added, and separated into aqueous layer and organic layer. The aqueous layer was acidified with 1N hydrochloric acid, extracted with ethyl acetate. The extract was combined with the former organic layer. The combined extract was washed with saturated brine, dried over anhydrous magnesium sulfate, subsequently, purified by silica gel column chromatography(chloroform:ethyl acetate=10:1), to thereby obtain 550 mg of the titled compound.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C@@H:23]([OH:26])[CH2:24][OH:25])=[CH:17][CH:16]=1)C1C=CC=CC=1>CO.[Pd]>[OH:26][C@@H:23]([CH2:24][OH:25])[CH2:22][NH:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:16][CH:17]=1
Reactant: O=C(NCCCCc1ccc(NC[C@@H](O)CO)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCCCc1ccc(NC[C@@H](O)CO)cc1
Yield: 89.9 %

Procedure:
The protected amine 700 (0.29 g, 0.77 mmol) was stirred at room temperature for 6 h in methanol (20 mL) with 10% Pd/C (129 mg, 50% wet) under hydrogen (1 atm). The catalyst was filtered off and the solvent was removed under reduced pressure to give amine 710 (0.165 g, 90%) as a clear oil. 1H NMR (300 MHz, CD3OD) δ 1.56 (m, 4H), 2.51 (t, 2H), 2.71 (t, 2H), 3.02 (m, 1H), 3.27 (m, 1H), 3.30 (m, 2H), 3.56 (m, 2H), 3.80 (m, 1H), 6.60 (d, 2H), 6.95 (d, 2H). m/z (ESI) 239 [C13H22N2O2+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH:18][C:30](=[O:31])[CH2:29][C:24]2[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:5])[CH3:6]
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1

Procedure:
2-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acid methyl ester was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 26.1, 26.2, 35.9, 43.0, 53.1, 53.3, 61.2, 102.5, 102.8, 103.0, 106.1, 112.3, 112.4, 112.5, 112.6, 132.0, 137.6, 138.8, 161.8, 162.0, 164.3, 164.4, 169.3, 169.4, 172.6; MS 437.20 m/z (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:31]([OH:33])=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].Cl.[CH2:35]([N:37]([CH2:40][CH2:41]Cl)[CH2:38][CH3:39])[CH3:36]>>[CH2:35]([N:37]([CH2:40][CH2:41][O:32][C:31](=[O:33])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH2:38][CH3:39])[CH3:36]
Reactant: CCN(CC)CCCl
Reactant: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)C(=O)O
Agent: Cl
Product: CCN(CC)CCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl

Procedure:
N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 2-[(N,N-diethyl)amino]ethyl ester was prepared from N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine and 2-[(N,N-diethyl)aminoethyl chloride hydrochloride using the general procedure described in example 28 and was obtained as an amorphous white solid. ES-HRMS m/e calcd for C30H37ClN4O5 (M+H) 569.2525, found 569.2530.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:31]([N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1)([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:37]5[CH:36]=[N:35][N:34]([CH:31]([CH3:33])[CH3:32])[CH:38]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)n1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 16-4), 1-isopropylpyrazole-4-boronic acid pinacol ester (153 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and potassium carbonate (163 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (217 mg, 68%) in an orange oily form.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:20])[NH:6][C:7]=1[C:8]1[C:9]([CH3:19])=[CH:10][C:11](C)=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14].CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1.CC1C=C(C)C(B2OC(C)(C)C(C)(C)O2)=CC=1C(OC)=O>>[OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:20])[NH:6][C:7]=1[C:8]1[CH:17]=[C:12]([CH:11]=[CH:10][C:9]=1[CH3:19])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(-c2[nH]c(C)nc2CO)c(C)cc1C
Agent: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2CO)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 236.3, except methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) was used in place of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:9][CH2:10][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[CH:9][CH2:10][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(NCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A suspension of 1.3 g. of p-[[3,3-bis(p-chlorophenyl)allyl]amino]benzoic acid, ethyl ester, 40 ml. of ethanol, and 4.6 ml. of 1N sodium hydroxide is heated at reflux for 28 hours, cooled, and then diluted with an equal volume of water. A 0.26 ml. portion of glacial acetic acid is added, and the mixture is cooled in ice. The solid is collected, washed with water, and recrystallized from absolute ethanol, giving 600 mg. of the desired product, m.p. 231°-235° C.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH2:26]>C1COCC1>[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH:26][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: COC(CN)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCC(OC)OC
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a stirred solution of methyl 2-chloro-3-nitrobenzoate (1.1 g, 4.9 mmol) from Step A above in THF (33 mL) was added triethylamine (0.8 mL, 6.0 mmol) followed by 2,2-dimethoxyethanamine (0.7 mL, 6.0 mmol) at room temperature. The reaction mixture was stirred overnight at reflux and then the suspension was concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 0% to 10% ethyl acetate in hexanes) to afford methyl 2-(2,2-dimethoxyethylamino)-3-nitrobenzoate (1.4 g, 98%): 1H NMR (500 MHz, DMSO-d6) δ 8.39 (t, J=4.5 Hz, 1H), 8.08-8.05 (m, 2H), 6.83 (t, J=8.0 Hz, 1H), 4.54 (t, J=5.0 Hz, 1H), 3.87 (s, 3H), 3.31 (s, 6H), 2.93 (t, J=5.0 Hz, 1H).