Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[CH:10]=[CH:24]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A solution of (S)-(−)-2-(tert-butoxycarbonylamino)-3-phenylpropanal (6.87 g, 27.56 mmol) and (carbethoxymethylene)triphenylphosphine (9.60 g, 27.56 mmol) in toluene (150 mL) was stirred and heated to 80° C. for 70 min. The product was isolated by flash column chromatography on silica gel using a gradient elution of 5-25% EtOAc/hexanes. Collection and concentration of the appropriate fractions yielded the compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.33-7.22 (m, 3H), 7.19-7.17 (m, 2H), 6.92 (dd, J=4.8, 15.6 Hz, 1H), 5.86 (dd, J=1.6, 15.6 Hz, 1H), 4.62 (br s, 1H), 4.52 (br s, 1H), 4.19 (q, J=7.2, 14.0 Hz, 2H), 2.95-2.90 (m, 2H), 1.40 (s, 9H), 1.30-1.25 (m, 3H); ES MS [M-100 (loss of BOC)+1]=220.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH:24]=[O:25])([CH2:18][CH2:19]2)[O:16][CH2:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH2:24][OH:25])([CH2:18][CH2:19]2)[O:16][CH2:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OCCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Temperature: -78 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a −78° C. solution of 110C compound (35 mg, 0.10 mmol) in DCM (2 mL) was added DIBAL-H (0.16 mL of a 1M solution in toluene; 16 mmol) and the solution was stirred at −78° C. for 2 h. The reaction was quenched with sat′d aq. NaH4Cl and CELITE® (200 mg) was added. The mixture was stirred at rt for 30 min, then was filtered through a 1:1 mixture of CELITE® and MgSO4 and concentrated in vacuo to give the title compound (22 mg, 77% yield). LCMS [M+H]+=339.4.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][C:12]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16][CH2:15]3)=[O:13])=[N:7][C:6]=2[CH:24]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC[N:36](CC)CC>C(Cl)Cl>[N:14]1([C:12](=[O:13])[CH2:11][S:10][C:8]2[S:9][C:5]3[CH:4]=[C:3]([NH:36][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:2]=[CH:24][C:6]=3[N:7]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: Nc1ccc2sc(SCC(=O)N3CCCc4ccccc43)nc2c1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccc2nc(SCC(=O)N3CCCc4ccccc43)sc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a 0° C. solution of compound 50 (0.22 g, 0.62 mmol) in dry CH2Cl2 (6 mL) was added benzoyl chloride (0.10 mL, 0.93 mmol) followed by dropwise addition of Et3N (0.26 mL, 1.86 mmol). The reaction was stirred overnight under N2 at room temperature. The reaction mixture was poured onto ice-water, and extracted with CH2Cl2 (3×20 mL). The combined organics extracts were washed with water (2×10 mL), and saturated NaCl (2×10 mL). Dried over MgSO4 and filtered. The solvent was removed under reduced pressure, and the product was purified by column chromatography (EtOAc/hexanes 1:1) to afford 55 as a white solid (132 mg, 46%); MS m/z: 460 (M+H)+. Anal. Calcd. For, C25H21N3O2S2: C, 65.33; H, 4.61; N, 9.14; S, 13.95. Found: C, 65.08; H, 4.64; N, 8.99; S, 13.69.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]([CH3:19])[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:8]=2)[N:5]=[C:4]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.N1C=CC=CC=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>C(Cl)Cl.O>[C:34]1([O:33][C:31](=[O:32])[NH:1][C:2]2[N:6]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([N:13]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH3:19])[N:8]=3)[N:5]=[C:4]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CN(C)CCN(C)c1nccc(-n2nc(C(C)(C)C)cc2N)n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CN(C)CCN(C)c1nccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 131.6 %

Procedure:
A solution of Intermediate 140b (129 mg, 0.41 mmol) in DCM (4.1 mL) was treated with pyridine (0.046 mL, 0.57 mmol) and the mixture was cooled 0° C. Phenyl chloroformate (0.066 mL, 0.53 mmol) was added and the resulting mixture was stirred at RT for 16 h. The mixture was cooled to 0° C. and treated with pyridine (0.013 mL, 0.16 mmol) then phenyl chloroformate (0.015 mL, 0.12 mmol) and stirred at RT for a further 1.75 h. Once again the mixture was cooled to 0° C. and treated with pyridine (0.013 mL, 0.16 mmol) then phenyl chloroformate (0.015 mL, 0.12 mmol) and stirred at RT for 1.75 h. The mixture was diluted with water and the phases were separated. The aqueous layer was extracted with DCM (×2) and the combined organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give a yellow gum (236 mg). Trituration with ether and filtration of the resulting solid gave the title compound as a white solid (75 mg, 39%). LCMS (Method 3): Rt 3.21 min, m/z 438.4 [MH+].
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[C:5]([F:10])=[CH:6][CH:7]=[CH:8][CH:9]=1.[NH:21]([CH3:46])[C@H:22]([C:26]([N:28]([CH3:45])[C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24].O>C1COCC1>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([N:21]([CH3:46])[C@H:22]([C:26]([N:28]([CH3:45])[C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:39])[CH3:40])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:13])[CH2:3][C:4]1[C:5]([F:10])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1F)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of Boc-Phe(2-F)-OH (0.20 g, 0.706 mmol), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.21 g, 0.578 mmol) and CMPI (0.20 g, 0.783 mmol) in THF (6 ml), TEA (0.30 ml, 2.15 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=60:1:0.05) to give Boc-Phe(2-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.33 g, 91%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]2[N:9]=[C:10]([NH:12][C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:15]=4[N:14]=3)[S:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH3:28][S:29][CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:28][S:29][CH2:30][CH2:31][NH:32][C:23]([C:21]1[CH:20]=[CH:19][C:16]2[N:17]([CH3:18])[C:13]([NH:12][C:10]3[S:11][C:7]4[CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:27]=[CH:26][C:8]=4[N:9]=3)=[N:14][C:15]=2[CH:22]=1)=[O:24]
Reactant: Cn1c(Nc2nc3ccc(S(C)(=O)=O)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CSCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CSCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(S(C)(=O)=O)cc3s1)n2C

Procedure:
2-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (2-methylsulfanyl-ethyl)-amide (41 mg) was prepared by following General Procedure F using 2-(6-methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (80 mg), 2-methylthio-ethylamine (0.2 ml), HBTU (76 mg), and DIEA (0.2 ml). LCMS: m/z 477.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH:6]=[C:7]([O:12]C)[C:8]=1[CH2:9][CH2:10][CH3:11].Cl.N1C=CC=CC=1.CCOCC>C(OCC)(=O)C>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:15]=[CH:14][C:5]1[CH:6]=[C:7]([OH:12])[C:8]([CH2:9][CH2:10][CH3:11])=[C:3]([OH:2])[CH:4]=1
Reactant: CCCc1c(OC)cc(C=Cc2ccccc2F)cc1OC
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(O)cc(C=Cc2ccccc2F)cc1O
Temperature: 200 °C
Yield: 95.9 %

Procedure:
A mixture of 2-(3,5-dimethoxy-4-1-propylphenyl)-1-(2-fluorophenyl)ethene (27B) (0.308 g, 1.03 mmol) and pyridine hydrochloride (0.72 g, 6.2 mmol) was heated at 200° C. for 4 h under a stream of argon. The reaction mixture was cooled to room temperature. 2NHCl (10 mL) and ether (15 mL) was added. The organic layer was separated and the aqueous layer was extracted with ether (3×10 mL). The extract was dried over anhydrous Na2SO4. Evaporation of ether followed by flash chromatography using 15% ethyl acetate in hexane afforded pure 5-[2-(2-fluorophenyl)ethenyl]-2-1-propyl-1,3-benzenediol (37B) (0.269 g, 95% yield) as an off-white solid. 1HNMR (CDCl3, ppm): δ 1.41 (d, J=7.2 Hz, 6H), 3.51 (qint., J=7.2 Hz, 1H), 5.01 (b, 2H), 6.56 (s, 2H), 6.98 (d, J=17.6 Hz, 1H), 7.0-7.3 (m, 4H), 7.60 (ddd, J=7.5, 7.5, 2.2 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[O:19][C:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:21][N:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[O:19][C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[CH:21][N:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1ncc(-c2cccs2)o1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1csc(-c2cnc(COc3ccc(CCCn4ccnc4)cc3)o2)c1
Yield: 90 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was reacted with 2-chloromethyl-5-(2-thienyl)oxazole to obtain 2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-(2-thienyl)oxazole. The yield was 90%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 75-76° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].C(NC(C)C)(C)C.C([Li])CCC.[Si:19]([O:26][CH:27]([C:37]([F:40])([F:39])[F:38])[CH2:28][CH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[CH3:30])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].CI>>[Si:19]([O:26][CH:27]([C:37]([F:38])([F:40])[F:39])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)([CH3:1])[CH3:30])([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[O-]
Reactant: CC(CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1ccccn1
Agent: [K+]
Agent: [Li]CCCC
Solvent: CI
Solvent: CC(C)NC(C)C
Product: CC(C)(CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1ccccn1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of 3.87 mL (3.87 mmol, 1.5 eq.) of potassium tert-butoxide (1.0 M solution in THF) and 542 μL (3.87 mmol, 1.5 eq.) of diisopropylamine, 1.55 mL (3.87 mmol, 1.5 eq) of n-butyl lithium (2.5 M solution in hexanes) was added dropwise at −75° C. The resulting mixture was allowed to warm to −50° C. over 15 minutes. Then the reaction mixture was treated with 860 mg (2.58 mmol) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro 1-methylbutyl]pyridine at −50° C. and the resulting mixture was stirred for 30 minutes at −50° C. The reaction mixture was cooled to −75° C. and treated with 482 μL (7.74 mmol) of methyl iodide and stirred for 1 minute. The reaction mixture was quenched with saturated NH4Cl solution, and the product was extracted into ether. The ethereal layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to give 555 mg (62%) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1,1-dimethylbutyl]pyridine as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8].[C:17]([Cu])#[N:18]>CN1CCCC1=O.CCOC(C)=O>[C:17]([C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8])#[N:18]
Reactant: N#C[Cu]
Reactant: CCOC(=O)CCCc1ccc(O)c(Br)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCc1ccc(O)c(C#N)c1
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-(3-bromo-4-hydroxyphenyl)butanoate (19.8 g, 69 mmol) in 172 mL of N-methyl-2-pyrrolidinone was added CuCN (6.49 g, 72.4 mmol). The solution was heated to reflux for 4 hours then cooled to room temperature. The reaction was diluted with EtOAc and washed twice with 5% HCl and once with brine, then dried over sodium sulfate and concentrated. Purified on silica gel using 60:40 hexanes:EtOAc as the elutant. The yield of ethyl 4-(3-cyano-4-hydroxyphenyl)butanoate was 9.84 g (61%): 1H-NMR (CDCl3) 7.67 (1H, s), 7.24-7.29 (2H), 7.94 (1H, d), 4.14 (2H, q), 2.59 (2H, dd), 2.34 (2H, dd), 1.91 (2H, m), 1.28 (3H, t).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][OH:17].N1C=CC=CC=1>O>[CH3:12][O:13][CH2:14][CH2:15][CH2:16][O:17][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCCO
Solvent: c1ccncc1
Solvent: O
Product: COCCCOS(=O)(=O)c1ccc(C)cc1

Procedure:
4-Methyl-benzenesulfonyl chloride (21 g, 110.0 mmol, 1.1 equiv.) was added at 0° C. to a solution of 3-methoxy-propan-1-ol (9 g, 100.0 mmol, 1.0 equiv.) in pyridine (16.1 ml, 200.0 mmol, 2.0 equiv.). After 1 hr at 0° C. a white solid was formed. It was diluted with water and extracted twice with ethyl acetate. The combined organics were washed with KHSO4/K2SO4 and brine, dried over Na2SO4, filtered, evaporated and crystallized from ether (hygroscopic) to give toluene-4-sulfonic acid 3-methoxy-propyl ester, 21.4 g, m/e 245.0 (MH+).
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[C:26]([C:30]1[O:34][C:33]([CH3:35])=[C:32]([C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:31]=1)([CH3:29])([CH3:28])[CH3:27].NC1C=CNN=1>O1CCCC1>[C:26]([C:30]1[O:34][C:33]([CH3:35])=[C:32]([C:36]2[CH:37]=[C:38]([NH:41][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:13])[NH:39][N:40]=2)[CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C1Nc2cc(F)ccc2/C1=C/O
Reactant: Cc1oc(C(C)(C)C)cc1-c1cc(N)[nH]n1
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: Cc1oc(C(C)(C)C)cc1-c1cc(NC=C2C(=O)Nc3cc(F)ccc32)[nH]n1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 5-(5-tert-butyl-2-methyl-furan-3-yl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one (0.033 gms.) is reacted with 0.089 gms. 5-(5-tert-butyl-2-methyl-furan-3-yl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (0.88 mL) to afford the named compound in the amount of 0.0362 gms.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)=[O:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(O)c([N+](=O)[O-])c2)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1[N+](=O)[O-]
Yield: 46.8 %

Procedure:
A mixture of 1-(tert-butoxycarbonyl)-4-(4-hydroxy-3-nitrobenzoyl)piperidine (1.50 g, 4.3 mmol), potassium carbonate (0.77 g, 5.6 mmol), and methyl bromoacetate (0.66 g, 4.3 mmol) in acetone (20 mL) was stirred at reflux for 18 h. The reaction mixture was cooled and evaporated in vacuo, and the residue partitioned between water (20 mL) and dichloromethane (20 mL). The organic layer was separated and washed with 1N NaOH (aq) (20 mL), water (20 mL), and brine (10 mL), dried (Na2SO4) and evaporated in vacuo to give crude product which was purified by chromatography on silica gel (˜20 g) eluting with 10–100% EtOAc in hexane to give the title compound (0.85 g, 47%) as a yellow oil. 1H NMR (CDCl3) δ: 1.47 (9H, s), 1.62–1.89 (4H, m), 2.91 (2H, m), 3.35 (1H, m), 3.82 (3H, s), 4.17 (2H, m), 4.88 (2H, s), 7.04 (1H, d, J=9 Hz), 8.13 (1H, dd, J=9, 2 Hz), 8.44 (1H, d, J=2 Hz).
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.P1(O)(OC2C=CC3C(C=2C2C4C(C=CC=2O1)=CC=CC=4)=CC=CC=3)=O>[F:12][C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:6]=[CH:7][C:2]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Fc1c(Br)cccc1C(F)(F)F
Reactant: C1CNCCN1
Agent: CC(C)(C)[O-]
Agent: O=P1(O)Oc2ccc3ccccc3c2-c2c(ccc3ccccc23)O1
Agent: [K+]
Solvent: Cc1ccccc1
Product: Fc1c(N2CCNCC2)cccc1C(F)(F)F
Temperature: 80 °C
Yield: 54.5 %

Procedure:
To a solution of 3-bromo-2-fluorobenzotrifluoride (1.72 g, 7.1 mmol) in toluene (50 ml) under nitrogen, was added piperazine (0.89 g, 10.6 mmol), potassium tert-butoxide (0.95 g, 9.9 mmol), b is (dibenzylideneacetone)palladium(0) (0.19 g, 0.21 mmol) and (+/−)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (0.13 g, 0.21 mmol). The resulting mixture was heated at 80° C. for 20 h. Filtration through a pad of celite and evaporation of the filtrate gave 2.1 g of crude product. The residue was purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (0.96 g). MS m/z (rel. intensity, 70 eV) 248 (M+, 23), 207 (10), 206 (bp), 190 (17), 163 (8).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]([NH:14][C@@H:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]([OH:18])=[O:17])=[O:13])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].Cl.Cl.[NH2:33][C@@H:34]([CH2:38][CH2:39][CH2:40][NH:41][C:42]([NH2:44])=[NH:43])[C:35]([NH2:37])=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C)C=O>[C:16]([OH:18])(=[O:17])[CH3:15].[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]([NH:14][C@@H:15]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:16]([NH:33][C@@H:34]([CH2:38][CH2:39][CH2:40][NH:41][C:42]([NH2:44])=[NH:43])[C:35]([NH2:37])=[O:36])=[O:17])=[O:13])=[CH:8][CH:9]=1)(=[NH:2])[NH2:3]
Reactant: N=C(N)NCCC[C@H](N)C(N)=O
Reactant: N=C(N)c1ccc(CC(C(=O)N[C@H](C(=O)O)C2CCCCC2)C2CCCCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)N)cc1)C1CCCCC1)C1CCCCC1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [3-(4-carbamimidoyl-phenyl)-2-cyclohexyl-propionylamino]-(S)-cyclohexyl-acetic acid (41 mg, 0.1 mmol, less polar diastereomer, example 1h) and 2-(S)-amino-5-guanidino-pentanoic acid amide dihydrochloride (24.6 mg, 0.1 mmol) in dimethylformamide (5 ml) were added HATU (39 mg, 0.1 mmol) and collidine (24.2 mg, 0.2 mmol) at 0° C. The mixture was stirred for 1 hour and then allowed to warm to room temperature. After evaporation, the residue was purified by chromatography on Sephadex LH20 employing n-butanol (17): glacial acetic acid (1): water (2) as eluent. Pure fractions were combined. The solvent was evaporated, the residue was taken up in water, and the aqueous solution was lyophilized. Yield: 50 mg (74%), MS m/z: 569.5 (M+H)+, 285.4 (M+2H)2+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]1)=[O:11].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1
Reactant: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Product: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 473 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH2:11][CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 90 °C
Yield: 63.4 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)propylamine (348 mg, 1.3 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (310 mg, 1.3 mmol) and DIPEA (1.1 mL, 6.4 mmol) in IPA (4 mL) was heated for 72 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% 2M NH3/MeOH in DCM) to afford 247 as a white solid (320 mg, 63%). LCMS (Method K): RT 3.17 min [M+H]+ 389.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.85 (1H, br s), 8.65 (1H, s), 8.15-8.03 (2H, m), 7.99 (1H, s), 7.84-7.76 (2H, m), 7.71 (1H, dd, J=8.75, 4.90 Hz), 7.55-7.48 (1H, m), 7.20-7.08 (2H, m), 5.73 (1H, s), 2.15-2.06 (1H, m), 2.05-1.95 (1H, m), 0.90 (3H, t, J=7.30 Hz)