Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH3:37][C:38]1[C:42](C(=O)C)=[C:41]([CH3:46])[N:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:39]=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:42]2[C:38]([CH3:37])=[N:39][N:40]([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:41]=2[CH3:46])[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1c(C)nn(-c2ccccc2)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(-c2ccccc2)c(C)c1-c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 37 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (47 mg, 37% yield).
Reaction SMILES: [N:1]#[C:2][NH2:3].Cl.[NH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]=2[CH:19]=1>C(O)C>[NH:5]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]=2[CH:19]=1)[C:2]([NH2:3])=[NH:1]
Reactant: N#CN
Reactant: CCOC(=O)c1cc2cc(N)ccc2o1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc2cc(NC(=N)N)ccc2o1
Temperature: 50 °C
Yield: 90 %

Procedure:
Ethanol (30 ml) and cyanamide (298 mg, 7.09 mmol) were added to hydrochloride (856 mg, 3.54 mmol) of ethyl 5-amino-2-benzofurancarboxylate, and the mixture was stirred with heating at about 50° C. for 24 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/3-3/1) to give 902 mg of ethyl 5-guanidino-2-benzofurancarboxylate as a colorless solid (90%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([N:26]2[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[C:27]2=[O:34])[CH:19]=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:31]([CH:28]1[CH2:29][CH2:30][N:26]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([F:25])([F:23])[F:24])=[C:16]([F:15])[CH:17]=2)[C:27]1=[O:34])=[O:32]
Reactant: O=C(O)C1CCN(c2ccc(C(F)(F)F)c(F)c2)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc(C(F)(F)F)c(F)c2)C1=O
Yield: 19.6 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxopyrrolidine-3-carboxylic acid (0.130 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.0389 g (20%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:28])[C@@H:16]([NH:18][C:19](=[O:27])[CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH3:17])[C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[NH2:29][C@@H:30]([CH2:37][CH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)[C:31]([C@@:33]1([CH3:36])[CH2:35][O:34]1)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[CH:38]1([CH2:37][C@H:30]([NH:29][C:11](=[O:12])[C@@H:10]([NH:14][C:15](=[O:28])[C@@H:16]([NH:18][C:19](=[O:27])[CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH3:17])[CH2:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([OH:1])[CH:3]=2)[C:31]([C@@:33]2([CH3:36])[CH2:35][O:34]2)=[O:32])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: Cc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)O)cc1O
Reactant: C[C@]1(C(=O)[C@@H](N)CC2CCCC2)CO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)N[C@@H](CC2CCCC2)C(=O)[C@@]2(C)CO2)cc1O
Temperature: 25 °C
Yield: 11 %

Procedure:
(S)-3-(3-Hydroxy-4-methylphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoic acid was dissolved in DMF (5 mL) and (S)-2-amino-3-cyclopentyl-1-((R)-2-methyloxiran-2-yl)propan-1-one (TFA salt, 0.40 g, 1.3 mmol), HATU (0.65 g, 1.9 mmol) and DIEA (0.5 mL) were added at 0° C. with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added and the two layers were separated. The aqueous phase was extracted with EtOAc (30 mL×3) and the combined organic phases were washed with brine (50 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/EtOAc/MeOH=20:10:1) to afford (S)-N-((S)-3-cyclopentyl-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-(3-hydroxy-4-methylphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanamide (150 mg, 11% yield over three steps). 1H NMR (300 MHz, DMSO-d6): δ 9.06 (s, 1H), 8.26 (d, J=7.2 Hz, 1H), 8.06 (d, J=8.7 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.61 (s, 1H), 6.53 (d, J=7.2 Hz, 1H), 4.51-4.39 (m, 1H), 4.30-4.15 (m, 2H), 3.69-3.61 (m, 4H), 3.17 (d, J=5.4 Hz, 1H), 3.00 (d, J=5.1 Hz, 1H), 2.90-2.81 (m, 3H), 2.42-2.30 (m, 4H), 2.04 (s, 3H), 1.91-1.42 (m, 7H), 1.41 (s, 3H), 1.30-1.02 (m, 6H). MS(EI) for C30H44N4O7, found 573.3 (MH)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:14][C@@H:15]([OH:48])[C@@H:16]([NH:36][C:37](=[O:47])[O:38][C@@H:39]3[C@H:46]4[C@H:42]([O:43][CH2:44][CH2:45]4)[O:41][CH2:40]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][Si](C(C)(C)C)(C)C)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C(O)(=O)C>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:14][C@@H:15]([OH:48])[C@@H:16]([NH:36][C:37](=[O:47])[O:38][C@@H:39]3[C@H:46]4[C@H:42]([O:43][CH2:44][CH2:45]4)[O:41][CH2:40]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCO[Si](C)(C)C(C)(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCO)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
(3R,3aS,6aR)-Hexahydro-furo[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-1-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)benzyl]-2-hydroxypropylcarbamate was treated with 1M tetra-n-butyl ammonium fluoride/tetrahydrofuran/acetic acid as described in step b (Example 213) to afford the title compound as a white solid. 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.38 (1H, quintuplet), 1.8 (2H, quintuplet), 1.9-2.0 (1H, m), 2.38 (1H, t), 2.6-2.8 (3H, m), 2.9 (1H, d), 2.96 (1H, dd), 3.3 (1H, br s) 3.4-3.6 (6H, m), 3.7 (1H, t), 3.8 (1H, dd), 3.9 (2H, t), 4.5 (1H, t), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.78 (2H, d), 7.0-7.1 (3H, m), 7.2 (1H, d), 7.25 (1H, s), 7.3 (1H, d); MS: 651 (MH+)
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13](=[O:36])[C@H:14]([CH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:31][CH2:32][CH2:33][NH2:34])=[C:25]([Cl:35])[CH:24]=1)[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:36])[C@H:14]([CH2:22][C:23]1[CH:24]=[C:25]([Cl:35])[C:26]([O:30][CH2:31][CH2:32][CH2:33][NH:34][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:27]([Cl:29])[CH:28]=1)[NH:15][C:16](=[O:21])[C:17]([F:20])([F:18])[F:19]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@H](Cc1cc(Cl)c(OCCCN)c(Cl)c1)NC(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](Cc1cc(Cl)c(OCCCNC(=O)c2ccccc2)c(Cl)c1)NC(=O)C(F)(F)F
Yield: 105.3 %

Procedure:
A solution of benzoyl chloride (94 mg, 0.669 mmol) in ethyl acetate (2 ml) was added dropwise to a two-layer solution of O-(3-aminopropyl)-3,5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester hydrochloride (209 mg, 0.461 mmol) and sodium bicarbonate (150 mg, 1.79 mmol) in ethyl acetate (3 ml)-water (2 ml) with stirring under ice cooling and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (20 ml) and the organic layer was separated, washed with brine and dried. The solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (n-hexane/ethyl acetate=2−1) to give O-(3-benzoylaminopropyl)-3,5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester (253 mg, 100%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].I[C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(c3ccc(C(F)(F)F)cc3)C2)c1
Yield: 35.9 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (35 mg, 0.08 mmol) in toluene (1.0 ml), 1-Iodo-4-trifluoromethyl-benzene (11.4 μl, 0.08 mmol), racemic-2-Ditbutylphosphino-1-1′binapthyl (14 mg, 0.035 mmol), and sodium t-butoxide ((10.0 mg, 0.01 mmol) were added and the reaction was bubbled with nitrogen for 20 minutes. The reaction was degassed with nitrogen and Pd (II) OAc) 8.0 mg, 0.01 mmol) was added. The reaction was microwaved at 120° C. for 30 minutes. The reaction was concentrated in vacuo, and purified by silica gel chromatography to give the product as a yellow oil (17 mg, 22%). Calcd for C33H35F6NO2 (M+H) 591.63, Found 592.3
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:3]=12.[CH3:17][C:18]1[C:26]([NH2:27])=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2>>[CH3:17][C:18]1[C:26]([NH:27][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[O:10][C:3]=23)=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2
Reactant: Cc1c(N)ccc2[nH]ccc12
Reactant: Clc1ccnc2cc(-c3ccccc3)oc12
Product: Cc1c(Nc2ccnc3cc(-c4ccccc4)oc23)ccc2[nH]ccc12

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-phenylfuro[3,2-b]pyridine (60.00 mg; 0.26 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (40.10 mg; 0.27 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one and was obtained as a brown oil (88 mg, 98%). (HPLC (method F): 96%, RT: 3.91 min); MS (m/z) 340 [M+H]+, RT: 2.7 min.
Reaction SMILES: N[C:2]1[C:3]([C:13]#[N:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[I:15]CI.N(OCCC(C)C)=O>C1COCC1.[Cu](I)I>[C:13]([C:3]1[C:2]([I:15])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:12])[CH:4]=1)#[N:14]
Reactant: ICI
Reactant: COC(=O)c1cc(N)c(C#N)cc1C
Agent: I[Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(I)c(C#N)cc1C
Temperature: 85 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
To a solution of methyl 5-amino-4-cyano-2-methylbenzoate (5.0 g, 0.0262 mol) in THF (100 mL) was added copper iodide (5.0 g, 0.0262 mol), diiodomethane (10.5 mL, 0.131 mol) and isoamyl nitrite (10.5 mL, 0.0786 mol). The reaction mixture was heated to 85° C. and stirred for 3 h, at which time it was cooled to room temperature. The heterogeneous mixture was filtered through a bed of celite, and the filter cake rinsed with ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography (100% hexanes to 2% diethyl ether in hexanes), then triturated with hexanes to afford methyl 4-cyano-5-iodo-2-methylbenzoate (3.7 g, 76%) as a white powder. 1H NMR (400 MHz, CDCl3): 8.39 (s, 1H), 7.50 (s, 1H), 3.94 (s, 3H), 2.56 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:6]=[C:5]2Cl.CN.C[CH2:23][N:24](CC)CC>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:6]=[C:5]2[NH:24][CH3:23]
Reactant: Cc1cc(Br)cc2c(Cl)nc(-c3cccnc3)nc12
Reactant: CCN(CC)CC
Agent: CN
Solvent: CC(C)O
Product: CNc1nc(-c2cccnc2)nc2c(C)cc(Br)cc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A mixture of 6-bromo-4-chloro-8-methyl-2-(pyridin-3-yl)quinazoline (200 mg, 0.60 mmol, 1.0 eq.), methylamine (81 mg, 1.20 mmol, 2.0 eq.) and Et3N (0.2 mL) in i-PrOH (10 mL) was stirred at 85° C. overnight. The resultant yellow precipitate was collected to afford 125 mg of vi-t as a beige solid (63.4%). LCMS m/z=328.8, 330.8 (M+1-1) (Method B) (retention time=1.95 min).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][N:37]1[C:41]([CH:42]=[O:43])=[CH:40][N:39]=[CH:38]1.C([Li])(CC)C>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([CH:42]([C:41]2[N:37]([CH3:36])[CH:38]=[N:39][CH:40]=2)[OH:43])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: Cn1cncc1C=O
Agent: [Li]C(C)CC
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3cncn3C)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl) silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3), 1-methyl-imidazole-5-carbaldehyde (116 mg, 1.06 mmol) and sec-butyllithium.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:35])[O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1>[C:24](=[O:35])([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH2:4][CH2:3]1)[O:25][C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1
Reactant: O=c1ccc(N2CCC(O)CC2)n[nH]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(c2ccc(=O)[nH]n2)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
To a solution of 6-(4-hydroxypiperidin-1-yl)pyridazin-3(2H)-one (3.9 g, 20 mmol) in pyridine (10 mL) was added DIPEA (3.87 g, 30.0 mmol) and 4-nitrophenyl carbonochloridate (6.03 g, 30 mmol) and the resulting mixture was stirred at 30° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM to DCM/MeOH=20/1) to afford the title compound (3.3 g, 46%) as a white solid. [LCMS: Rt=1.47 min, m/z 361.1 (M+H)+].
Reaction SMILES: [CH2:1](OC(=O)[C@H](CCC(OCC1C=CC=CC=1)=O)N)[C:2]1[CH:7]=CC=[CH:4][CH:3]=1.[NH2:25][C@H:26]([C@H:31]([CH2:33][C:34](=[O:36])[OH:35])[OH:32])[CH2:27][CH:28]([CH3:30])[CH3:29].[NH2:37][C@H:38]([C:40]([OH:42])=[O:41])[CH3:39].N[C@H]([C@H](CC(=O)O)O)CC(C)C.[NH2:55][C@H:56]([C:63]([OH:65])=[O:64])[CH2:57][C:58]1[N:62]=[CH:61][NH:60][CH:59]=1.[C:66]([O:70][C:71]([NH:73][C@H:74]([C:82]([OH:84])=[O:83])[CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)=[O:72])([CH3:69])([CH3:68])[CH3:67]>[OH-].[OH-].[Pd+2].CO>[NH2:55][C@H:56]([C:63]([OH:65])=[O:64])[CH2:57][C:58]1[N:62]=[CH:61][NH:60][CH:59]=1.[C:66]([O:70][C:71]([NH:73][C@H:74]([C:82]([OH:84])=[O:83])[CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)=[O:72])([CH3:69])([CH3:67])[CH3:68].[NH2:37][CH:38]([CH2:39][CH2:1][CH:2]([CH2:3][CH3:4])[CH3:7])[C:40]([OH:42])=[O:41].[NH2:25][C@H:26]([C@H:31]([CH2:33][C:34](=[O:35])[OH:36])[OH:32])[CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: C[C@H](N)C(=O)O
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)C[C@H](N)[C@@H](O)CC(=O)O
Solvent: CO
Product: CCC(C)CCC(N)C(=O)O
Reaction time: 2 h

Procedure:
A mixture of [N-(t-butyloxycarbonyl)-phenylalanine]-histidine-statine-alanine-statine-glutamic acid dibenzyl ester (90 mg., 0.077 mmoles), 20% Pd(OH)2/C catalyst(45 mg.) and methanol (10 ml.) was hydrogenated for 2 hours at room temperature and 50 psi H2. The reaction mixture was then filtered to remove the catalyst and the filtrate evaporated to yield a foam (72 mg.). This foam was triturated with ether and dried to yield a purified [N-(t-butyloxycarbonyl)-phenylalanine]-histidine-statine-glutamic acid foam (51 mg., 72% yield, 1H NMR, CDCl3, 1.5 delta, 9H s [BOC]).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1)=[O:8])[CH3:5].Cl[Sn]Cl>CO>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH:12]=[C:13]([NH2:15])[CH:14]=1)=[O:8])[CH3:5]
Reactant: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CO
Product: COCC(C)NC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Yield: 90.2 %

Procedure:
To a stirred solution of 4′-methyl-5-nitro-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (39 mmol) in 250 ml methanol was added SnCl2 (117 mmol) in one portion at room temperature. The reaction mixture was heated to reflux for 3 hours. Solvent was removed under reduced pressure and the residue was diluted with ethyl acetate and treated with saturated NaHCO3 solution. Solids were filtered off and the filtrate was washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vaccuo to give 5-amino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide as a yellow oil (10.5g, 90.3%). MS (M+H)=299.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.C1(CC[N:27]2[CH:31]=[C:30]([C:32]3S[C:34]([C:38](O)=O)=[C:35](C)[N:36]=3)N=N2)CC1.N1C=CC=C(CN)C=1>>[CH:7]1([CH2:2][CH2:1][N:8]2[CH:12]=[C:11]([C:13]3[S:14][C:15]([C:19]([NH:27][CH2:31][C:30]4[CH:32]=[N:36][CH:35]=[CH:34][CH:38]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[N:10]=[N:9]2)[CH2:6][CH2:5]1
Reactant: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)O
Reactant: Cc1nc(-c2cn(CCC3CC3)nn2)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(-c2cn(CCC3CC3)nn2)sc1C(=O)NCc1cccnc1
Yield: 19 %

Procedure:
Following the procedure as described in Example 4, making variations as necessary to replace 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid with 2-(1-(2-cyclopropylethyl)-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 19% yield: mp 124-125° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.52 (s, 1H), 8.09 (s, 1H), 7.33-7.22 (m, 2H), 6.33 (t, J=5.7 Hz, 1H), 4.62 (d, J=5.7 Hz, 2H), 4.48 (t, J=7.0 Hz, 2H), 2.71 (s, 3H), 1.82 (q, J=7.0 Hz, 2H), 0.71-0.56 (m, 1H), 0.52-0.43 (m, 2H), 0.08-0.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 161.9, 158.3, 157.3, 149.3, 149.1, 142.4, 135.7, 133.6, 124.1, 123.7, 121.8, 51.1, 41.6, 35.1, 17.4, 8.1, 4.3; MS (ES+) m/z 369.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[C:26]([F:27])=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](C(N)=O)[CH:17]=3)=[C:13]([F:28])[CH:12]=2)=[O:9])[C:4](=[O:29])[N:3]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CC#[N:54]>CCOC(C)=O>[NH2:54][C:18]1[CH:17]=[C:16]([O:15][C:14]2[C:13]([F:28])=[CH:12][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:29])[N:3]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[C:26]([F:27])[CH:25]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(C(N)=O)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Reactant: CC#N
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(N)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2,5-difluorophenoxy)picolinamide (80 mg, 0.17 mmol) in EtOAc (2 mL), CH3CN (2 mL), and H2O (1 mL) was added PhI(OAc)2 (70 mg, 1.2 mmol). The reaction was stirred at 0° C. for 30 minutes, then warmed up to rt and continued to stir for 8 hours. The mixture was filtered through a CELITE® pad, which was washed with EtOAc (30 mL). The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=20/1) to afford the tile compound as a white solid (51 mg, 68%).