Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4](=[NH:8])OCC)#[N:2].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C(O)C>[NH2:8][C:4]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[CH:3][C:1]#[N:2]
Reactant: CCOC(=N)CC#N
Reactant: C1COCCN1
Solvent: CCO
Product: N#CC=C(N)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In anhydrous ethanol (10 ml) was dissolved ethyl 2-cyanoacetimidate (1.0 g), followed by addition of morpholine (0.78 g). The mixture was stirred at room temperature for 4 hours, and the separated crystals were collected by filtration. This crystal crop was used as it was in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:9]1[N:14]=[C:13]([CH2:15][C@@H:16]2[C@H:20]([O:21][CH2:22][CH:23]=O)[CH2:19][N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:17]2)[CH:12]=[C:11]([CH3:32])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][NH2:48].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C:9]1[N:14]=[C:13]([CH2:15][C@@H:16]2[C@H:20]([O:21][CH2:22][CH2:23][NH:48][CH2:47][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[F:40])[CH2:19][N:18]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:17]2)[CH:12]=[C:11]([CH3:32])[CH:10]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NCc1ccccc1F
Reactant: Cc1cc(C[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2OCC=O)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2OCCNCc2ccccc2F)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Yield: 97 %

Procedure:
To a solution of aldehyde 6 (100 mg, 0.18 mmol) in DCM (4 mL) was added (2-fluorophenyl)methanamine (45 mg, 0.36 mmol), triethylamine (11 μL, 0.36 mmol), followed by NaHB(OAc)3 (100 mg, 0.45 mmol). The reaction mixture was stirred for an additional 3 hand then concentrated. The crude product was purified by flash column chromatography (EtOAc/hexanes, 1:1, Rf=0.15) to yield 7a (115 mg, 91%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 1.43-1.44 (s, 27H), 2.29-2.30 (m, 3H), 2.60-2.75 (m, 1H), 2.76-2.85 (m, 2H), 2.92-3.00 (m, 1H), 3.05-3.14 (m, 1H), 3.20-3.50 (m, 5H), 3.52-3.70 (m, 2H), 3.72-3.80 (m, 1H), 3.91 (s, 2H), 6.84-6.85 (d, J=8.0 Hz, 1H), 6.89-6.91 (d, J=10.0 Hz, 1H), 7.02-7.06 (dd, J=9.0, 9.5 Hz, 1H), 7.10-7.13 (dd, J=7.0, 7.5 Hz, 1H), 7.20-7.30 (m, 1H), 7.35-7.40 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 20.9, 24.7, 27.9, 28.47, 28.50, 29.7, 34.6, 34.7, 36.6, 42.6, 43.3, 46.8, 48.2, 48.8, 49.1, 50.3, 50.8, 68.0, 68.2, 78.7, 79.2, 79.3, 79.4, 82.8, 115.2, 115.3, 115.4, 115.5, 119.5, 119.6, 122.8, 124.17, 124.19, 128.89, 128.92, 128.95, 128.99, 130.46, 130.51, 130.55, 149.6, 151.4, 151.5, 151.8, 154.5, 154.8, 159.08, 159.14, 160.3, 162.2; LC-TOF (M+H+) calcd for C35H52FN4O7 659.3820. found 659.3818.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)[N:18]=[N:19][C:14]3=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:31]([N:33](C(C)C)C(C)C)[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.C(N)C>CN(C=O)C.O>[CH2:31]([NH:33][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)[N:18]=[N:19][C:14]3=[CH:13][CH:12]=2)=[CH:10][C:2]=1[F:1])[CH3:32]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Reaction time: 0.08 h
Yield: 65.7 %

Procedure:
To a solution of example 13 (0.100 g, 0.250 mmol) in DMF (0.7 ml), N-ethyldiisopropylamine (0.064 g, 0.50 mmol) and HATU (0.095 g, 0.250 mmol) were added and stirred for 5 min. Ethylamine hydrochloride (0.020 g, 0.250 mmol) was added at RT and the reaction mixture was stirred for 12 h. Water was added to the reaction mixture and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as a yellow solid (0.070 g, 66%). M.P.: 207-209° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.71 (d, J=8.7 Hz, 1H), 8.41 (m, 1H), 8.37 (d, J=7.6 Hz, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.17 (m, 2H), 8.04 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.84 (dd, J=8.7, 1.9 Hz, 1H), 7.77 (t, J=7.9 Hz, 1H), 7.54 (dd, J=8.3, 4.1 Hz, 1H), 6.23 (s, 2H), 3.29 (m, 2H), 1.4 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:14]1[N:15]=[CH:16][N:17]([C:19]2[CH:20]=[C:21]([NH2:26])[CH:22]=[CH:23][C:24]=2[CH3:25])[CH:18]=1)[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C[O:38][C:39](=O)[C:40]1[CH:45]=[C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:43]=[CH:42][C:41]=1[O:50][CH3:51].C([O-])(O)=O.[Na+]>C1COCC1>[C:46]([C:44]1[CH:43]=[CH:42][C:41]([O:50][CH3:51])=[C:40]([CH:45]=1)[C:39]([NH:26][C:21]1[CH:22]=[CH:23][C:24]([CH3:25])=[C:19]([N:17]2[CH:18]=[C:14]([C:4]3[CH:5]=[N:6][N:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:3]=3[CH2:1][CH3:2])[N:15]=[CH:16]2)[CH:20]=1)=[O:38])([CH3:49])([CH3:47])[CH3:48]
Reactant: CCc1c(-c2cn(-c3cc(N)ccc3C)cn2)cnn1-c1ccccc1
Reactant: COC(=O)c1cc(C(C)(C)C)ccc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1c(-c2cn(-c3cc(NC(=O)c4cc(C(C)(C)C)ccc4OC)ccc3C)cn2)cnn1-c1ccccc1
Reaction time: 0.08 h
Yield: 50.5 %

Procedure:
3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-phenylamine (Example 3) (80 mg, 0.23 mmol) was dissolved in THF (5 mL) under N2 and 0.9 mL of 1 M LiHMDS (0.9 mmol) was slowly added. After stirring for 5 min, a solution of 51.8 mg (0.23 mmol) of 5-tert-butyl-2-methoxy-benzoic acid methyl ester in 5 mL of THF was added. The mixture was stirred at for 45 min, then saturated NaHCO3 (10 mL) was slowly added. The resulting mixture was then extracted with CH2Cl2 (100 mL). Chromatography (30 to 100% EtOAc in hexanes) provided the title compound as a tan foam (62 mg, 50%). ESI MS m/z 534 [C33H35N5O2+H]+.
Reaction SMILES: C(N(CC)CC)C.C(O[C@H:12]1[NH:15][C:14](=[O:16])[C@@H:13]1[C@H:17]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][O:19][SiH:20]([CH3:22])[CH3:21])(=O)C.[N+:27](=[C:29]([C:36](=[O:38])[CH3:37])[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])=[N-:28].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCl>[C:23]([C@@H:17]([C@H:13]1[C@@H:12]([CH2:37][C:36](=[O:38])[C:29]([C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])=[N+:27]=[N-:28])[NH:15][C:14]1=[O:16])[CH2:18][O:19][SiH:20]([CH3:21])[CH3:22])([CH3:24])([CH3:25])[CH3:26]
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(C)=O
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](CO[SiH](C)C)C(C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)C(=[N+]=[N-])C(=O)C[C@H]1NC(=O)[C@H]1[C@@H](CO[SiH](C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
7.2 ml (52 mmol - 2.6 equivalents) of triethylamine are added to a solution, which has been cooled to 0° C., of 5.75 g (20 mmol) of (3R,4R)-4-acetoxy-3-[(1R)-1-tert.-butyldimethylsilyloxyethyl]azetidin-2-one [S. Oida et al. Chem. Pharm. Bull. 29 2899 (1981); M. Shiozaki et al. Tetrahedron 39 2399 (1983)] and 4.37 g (26 mmol - 1.3 equivalents) of allyl 2-diazo-3-oxobutanoate in 190 ml of anhydrous dichloromethane, and then 9.3 ml (48 mmol - 2.4 equivalents) of trimethylsilyl trifluoromethanesulphonate are added dropwise. The cooling bath was removed, and the mixture was stirred at room temperature for 1 h, 1.55 ml (8 mmol - 0.4 equivalent) of trimethylsilyl trifluoromethanesulphonate were added, and the mixture was stirred for a further 0.5 h at room temperature. The reaction solution was then poured into a mixture of cold, saturated NaHCO 3 solution and ethyl acetate, and extraction with ethyl acetate was carried out, and the combined organic extracts were washed with saturated NaCl solution and dried over MgSO4. The solvent was evaporated in vacuo, and the residue was filtered through 150 g of silica gel (toluene:ethyl acetate 4:1). 6.4 g (81%) of the title compound were obtained as pale crystals, melting point: 66° C., Rf: 0.33 (toluene:ethyl acetate 7:3) [α]D20 =59.2° (c 0.969, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12]([N:14]3[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][CH2:21][O:22][CH3:23])[CH2:15]3)=[N:13][C:4]=2[CH:3]=1.C=O.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:28])[C@@H:16]([CH2:20][CH2:21][O:22][CH3:23])[CH2:15]3)=[N:13][C:4]=2[CH:3]=1
Reactant: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sccc32)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sccc32)CCN1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.4 %

Procedure:
Combine (S)-7-chloro-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (571.5 mg, 1.52 mmol), formaldehyde (135.4 μL, 1.67 mmol, 37% in water), and dichloromethane (20.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (482.0 mg, 2.27 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (90:10) to give 418.3 mg (71%) of the title compound as a brown foam: mass spectrum (ion spray): m/z=391.1 (M+1).
Reaction SMILES: [Cl:1][C@@H:2]1[CH2:15][C@@H:14]([O:16]C2CCCCO2)[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([O:33]C2CCCCO2)[CH:26]([CH3:32])[CH2:27]/[CH:28]=[C:29](\[Cl:31])/[CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)(=O)C.O.O1CCCC1>[Cl:1][C@@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[CH:26]([CH3:32])[CH2:27]/[CH:28]=[C:29](\[Cl:31])/[CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: C/C(Cl)=C/CC(C)[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@H](Cl)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: C/C(Cl)=C/CC(C)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@H](Cl)C[C@H]1O
Yield: 59.1 %

Procedure:
Under argon, 427 mg of (5Z,13E,18Z)-(8R,9R,11R,12R,15S,16RS)-9,19-dichloro-16-methyl-11,15-bis(tetrahydropyran-2-yloxy)-5,13,18-prostatrienoic acid was stirred at room temperature for 16 hours with 9 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10). The mixture was then evaporated under vacuum and the residue purified by column chromatography on silica gel with hexane/20-80% ethyl acetate, thus producing 180 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3Br)=[CH:4][CH:3]=1.Cl.[C:29]([N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC([O-])(C)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[C:29]([N:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([CH:8]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[C:14]([OH:19])[CH:13]=2)[CH2:39][CH2:38]1)(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Reactant: NC1CCN(C(=O)c2ccccc2)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: O=C(c1ccccc1)N1CCC(Nc2cc(O)nc3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), 1-benzoylpiperidin-4-amine hydrochloride (118 mg, 0.49 mmol, 1.50 equip), Pd2(dba)3 (30.0 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip), KOt-Bu (73 mg, 0.65 mmol, 2.00 equip), and 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were removed by filtration. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 4-[(1-benzoylpiperidin-4-yl)amino]-6-[bis(4-chlorophenyl)methyl]quinolin-2-ol as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]([C:17](=[O:40])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]3[CH2:34][CH2:33][CH2:32][CH2:31][C:30]4[CH:35]=[CH:36][CH:37]=[CH:38][C:29]3=4)=[O:27])=[CH:22][C:21]=1[CH3:39])[CH2:5][C:6](=[O:16])[N:7]2[CH2:12][C:13](O)=[O:14].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+].[Cl-].[NH4+]>C1COCC1.O>[CH3:39][C:21]1[CH:22]=[C:23]([C:26]([N:28]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]3[CH:35]=[CH:36][CH:37]=[CH:38][C:29]2=3)=[O:27])[CH:24]=[CH:25][C:20]=1[CH2:19][NH:18][C:17]([N:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[F:1])[N:7]([CH2:12][CH2:13][OH:14])[C:6](=[O:16])[CH2:5]1)=[O:40]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CC(=O)O)c2cccc(F)c21
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CCO)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {5-fluoro-4-[2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)benzylcarbamoyl]-2-oxo-3,4-dihydro-2H-quinoxalin-1-yl}acetic acid from Example 8 (70 mg, 0.13 mmol) in THF (4.0 ml) was added N-methylmorpholine (18 μl, 0.18 mmol. The solution was cooled in an ice/water bath and isobutyl chloroformate (23 μl, 0.18 mmol) was added. The mixture was stirred in the ice/water bath for 1 h, filtered and added to a solution of sodium borohydride (12 mg, 0.32 mmol) in water (1.0 ml) in an ice/water bath. The mixture was allowed to warm to room temperature slowly and stirred at room temperature for 1 h. Saturated ammonium chloride (1 ml) was added and the mixture was evaporated in vacuo. The residue was taken up in water and extracted with chloroform. The organic phase was washed with brine, dried and evaporated in vacuo to give a white solid; yield 56 mg, 81%.
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:11]=3[C:12]=2[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:35]([O:37][C:38](=[O:42])[CH2:39][CH2:40][NH2:41])[CH3:36].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([NH:41][CH2:40][CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:42])=[O:30])=[CH:32][CH:33]=2)[C:8]2[O:9][C:10]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:11]=3[C:12]=2[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCN
Reactant: COCCOCc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2COCCOC)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a mixture of 4-[(cyclohexyl{5-fluoro-3-[(2-methoxyethoxy)methyl]-1-benzofuran-2-yl}methyl)amino]benzoic acid (200 mg) synthesized above, β-alanine ethyl ester hydrochloride (101 mg), 1-hydroxybenzotriazole monohydrate (101 mg), triethylamine (184 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (126 mg), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (216 mg, 89%) as a pale-yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.CC1N([C:24]([C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])C1>O1CCCC1.CCCCCC.O>[Cl:32][C:31]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:24](=[O:25])[CH2:19][C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: Cc1ccncc1
Reactant: CC1CN1C(=O)c1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=C(Cc1ccncc1)c1ccccc1Cl
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
To a stirred solution of diisopropylamine (15.4 mL) in dry tetrahydrofuran (100 mL) cooled at −50° C., was added a solution of 1.6 M n-butyllithium in hexane (69 mL) dropwise. After addition, the resulting mixture was stirred for 10 min at the same temperature, followed by the addition of a solution of γ-picoline (20 g) in dry tetrahydrofuran (10 mL) at −30° C. After an additional 1 h stirring, a solution of N-(2-chlorobenzoyl)propyleneimine (20 g) in dry tetrahydrofuran (10 mL) was added dropwise to the resulting mixture at −10° C. After addition the mixture was stirred for another 2 h at ambient temperature. Water (100 mL) was added to the mixture and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated under reduced pressure. The residue was purified using silica-gel column chromatography (hexane-ethyl acetate, 1:1) to give the title compound (16.4 g, yield 71%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C@@H:6]([CH2:10][NH:11][C:12](=[O:39])[CH2:13][C@@H:14]([C:29]([N:31]([CH:36]2[CH2:38][CH2:37]2)[CH2:32][C:33]([OH:35])=O)=[O:30])[NH:15][S:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)(=[O:18])=[O:17])[CH2:5]1)(=[NH:3])[NH2:2].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N1CCOCC1)C.[ClH:81]>CN(C=O)C>[ClH:81].[NH2:2][C:1](=[NH:3])[N:4]1[CH2:9][CH2:8][CH2:7][C@@H:6]([CH2:10][NH:11][C:12](=[O:39])[CH2:13][C@H:14]([NH:15][S:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)(=[O:18])=[O:17])[C:29]([N:31]([CH:36]2[CH2:38][CH2:37]2)[CH2:32][C:33]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[O:35])=[O:30])[CH2:5]1
Reactant: N=C(N)N1CCC[C@@H](CNC(=O)C[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N(CC(=O)O)C2CC2)C1
Reactant: C1COCCN1
Agent: CCN1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)N1CCC[C@@H](CNC(=O)C[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N(CC(=O)N2CCOCC2)C2CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g of N-[N4-[[(S)-1-amidino-3-piperidinyl]methyl]-N2-(2-naphthylsulfonyl)-L-asparaginyl]-N-cyclopropylglycine (Example 4a) is dissolved in 10 ml of DMF, treated with 0.2 ml of morpholine, 0.8 g of BOP and 1.1 ml of 4-ethylmorpholine and stirred at room temperature overnight. The reaction mixture is treated with 20 ml of 1N hydrochloric acid, evaporated and the residue is chromatographed on a RP-18 column with a water-acetonitrile gradient. There is obtained 0.5 g of (S)-N4-[(S)-1-(amino-imino-methyl)-piperidin-3-ylmethyl]-N1-cyclopropyl-N1-morpholin-4-ylcarbonylmethyl-2-(naphthalen-2-ylsulfonylamino)-succinamide hydrochloride (1:1), MS (ISP): 628.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:11]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:12][C:13]([CH3:24])=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:37][C:38]1[N:43]=[C:42](Cl)[C:41]([Cl:45])=[CH:40][N:39]=1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Cl:37][C:38]1[N:43]=[C:42]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]3[C:11]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[CH:12][C:13]([CH3:24])=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:15]=3)[CH:5]=[CH:6][CH:7]=2)[C:41]([Cl:45])=[CH:40][N:39]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Cc1cc(N2CCOCC2)c(CCc2cccc(N)c2)cc1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCOCC2)c(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)cc1NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 26.9 %

Procedure:
tert-Butyl {5-[2-(3-aminophenyl)ethyl]-2-methyl-4-morpholin-4-ylphenyl}carbamate (31 mg, 0.08 mmol) and potassium carbonate (16 mg, 0.11 mmol) were stirred in N,N-dimethylformamide (1 mL) and 2,4,5-trichloropyrimidine (9 μL, 0.08 mmol) was added. The mixture was stirred for 16 hours (or 16 h) and diluted with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate and evaporated to give the desired compound (12 mg, 14%). LCMS for C28H34NCl2N3O3 (M+H)+: m/z=558.1.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[CH:15]=[C:16]([C:31]#[N:32])[C:17]2[CH:18]=[CH:19][CH:20]=[N:21][C:22]=2[C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[F:30][C:26]1[CH:25]=[C:24]([C:23]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]([C:31]#[N:32])=[CH:15][C:14]=2[CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:29]=[CH:28][CH:27]=1
Reactant: CC(N)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1

Procedure:
A mixture of 6-bromo-9H-purine (0.0246 g, 0.124 mmol), 7-(1-aminoethyl)-8-(3-fluorophenyl)quinoline-5-carbonitrile (0.018 g, 0.062 mmol), and N,N-diisopropylethylamine (0.0216 mL, 0.124 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C23H17FN7 (M+H)+: m/z =410.2; Found: 410.1.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1ccc(N2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
The crude 4-(4-Chloro-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.10 g, 10.0 mmol) was dissolved in methylene chloride (1 mL) and treated with 4 N HCl/dioxane (10 mL, 40 mmol). The solution was stirred at rt for 1 hour, The reaction was concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine, dried over MgSO4, and evaporated to yield 1.00 g (48%) of the title compound. 1H-NMR (CDCl3) δ: 1.90 (2H, m), 2.23 (1H, brs), 2.83 (2H, m), 3.02 (2H, m), 3.54 (4H, m), 6.58 (2H, d, j=9.3 Hz), 7.13 (2H, d, j=9.3 Hz). ESI-MS m/z: 211 (M+1), FAS method rt: 1.04 min.