Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:29][C:11]3[N:12]([CH3:28])[C:13](=[O:27])[N:14]([CH2:17][CH2:18][CH2:19][O:20]C4CCCCO4)[C:15](=[O:16])[C:10]=3[C:9]=2[CH:30]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[OH:31])[CH:5]=[CH:6][CH:7]=1>Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:29][C:11]3[N:12]([CH3:28])[C:13](=[O:27])[N:14]([CH2:17][CH2:18][CH2:19][OH:20])[C:15](=[O:16])[C:10]=3[C:9]=2[CH:30]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[OH:31])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(-c3cccc(Cl)c3)sc21
Agent: Cl
Solvent: CO
Product: Cn1c(=O)n(CCCO)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(-c3cccc(Cl)c3)sc21
Yield: 47 %

Procedure:
A solution of 6-(3-chlorophenyl)-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetra hydro-2H-pyran-2-yl)oxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 0.052 mmol) in 2N HCl/MeOH (5 mL) was stirred at RT for 1 h. The reaction was concentrated to a residue which was purified by Prep HPLC to give 6-(3-chlorophenyl)-5-((4-chlorophenyl) (hydroxy)methyl)-3-(3-hydroxypropyl)-1-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (12 mg, 46.8% yield) as a white solid. 1H NMR (DMSO-d6) δ: 7.53-7.36 (m, 3H), 7.29 (t, J=7.2 Hz, 3H), 7.19 (d, J=8.4 Hz, 2H), 6.32 (d, J=9.1 Hz, 1H), 6.14 (d, J=9.0 Hz, 1H), 4.47 (t, J=5.2 Hz, 1H), 3.92 (t, J=7.3 Hz, 2H), 3.51 (s, 3H), 3.42 (dd, J=11.6, 6.2 Hz, 2H), 1.68 (d, J=6.4 Hz, 2H). LCMS: [M+-OH] 473 and TR=3.107 min.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:15](O)[C:16]3[C:21]([CH3:22])=[CH:20][C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][C:17]=3[CH3:31])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[CH:4][CH:3]=1.C(O)(=O)C.[H][H]>CO.[Pd].[C]>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[CH:18][C:17]=2[CH3:31])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(O)c2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1Cc1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(Cc2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1Cc1ccc(F)cc1
Yield: 78.8 %

Procedure:
590 mg of tert-butyl 4-[[3-(4-fluorobenzyl)-4-methoxyphenyl](hydroxy)methyl]-3,5-dimethylphenylcarbamate (Example VIII), 24 mg of Pd/carbon (10%) and a drop of acetic acid are hydrogenated in 10 ml of methanol with hydrogen at atmospheric pressure for 4 h. The suspension is filtered through kieselguhr. The filtrate is concentrated in a rotary evaporator. Chromatography (cyclohexane/ethyl acetate=6:1) affords 449 mg (77%) of tert-butyl 4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:17])[C:5]([NH:8][N:9]=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[N:6][CH:7]=1.[C:18]([C:22](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:23])(OC)=[O:19]>O1CCOCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([F:17])[C:5]([N:8]2[C:18](=[O:19])[C:22]([CH3:23])=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: COC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(C=NNc1ncc(Cl)cc1F)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCCCCC
Product: Cc1c(C(F)(F)F)cnn(-c2ncc(Cl)cc2F)c1=O
Temperature: 50 °C

Procedure:
A solution of 8.09 g 3((5-chloro-3-fluoro-pyridine-2-yl) -hydrazono)-1,1,1-trifluoro-propan-2-one and 11.5 g 1-carbomethoxyethylidene triphenylphosphine in 200 ml dioxane was stired for 30 min. at 20° C. and then heated until complete conversion at 50° C. The reaction mixture was diluted with hexane, filtered from solid triphenylphosphine oxide through silicagel and evaporated. Further purification of the residue on silicagel (ethyl acetate-hexane 3:7) led to the desired product with m.p. 91-93° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH2:7]([O:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=1)[CH3:8].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:7]([O:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH:13]=1)[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1cccc(CN)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(CNS(C)(=O)=O)c1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
Methanesulfonyl chloride (2.6 mL, 34 mmol) was slowly added to a solution of (3-aminomethyl-phenyl)-acetic Acid ethyl ester hydrochloride (7.31 g, 34 mmol) and triethylamine (9.8 mL, 70 mmol) in CH2Cl2 (100 mL) at 0° C. The mixture was stirred for 1 h and 1N aqueous HCl solution was added. The aqueous solution was extracted with CH2Cl2 (3×) and the combined organic extracts were washed with brine. The organic solution was dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (1:1 hexanes:EtOAc) provided the title sulfonamide (8.56 g) as a clear and colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.34-7.21 (m, 4H), 4.70 (broad, 1H), 4.29 (d, 2H), 4.12 (q, 2H), 3.60 (s, 2H), 2.86 (s, 3H), 1.24 (t, 3H).
Reaction SMILES: BrCCCC#CC1C=C[C:10]([NH:13][C:14]([NH:16][CH2:17][C:18]2[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]3[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:21]3=[N:22][C:23]=2[CH2:24][CH3:25])=[O:15])=[CH:9]C=1.NC1C=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][N:56]([CH2:64][C@@H:65]([C:74]2[CH:83]=[CH:82][C:81]([O:84][C:85]([O:87][C:88]([CH3:91])([CH3:90])[CH3:89])=[O:86])=[C:80]3[C:75]=2[CH:76]=[CH:77][C:78]([O:92][C:93]([O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:94])=[N:79]3)[O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[CH:41][CH:40]=1>>[C:96]([O:95][C:93]([O:92][C:78]1[CH:77]=[CH:76][C:75]2[C:80](=[C:81]([O:84][C:85]([O:87][C:88]([CH3:91])([CH3:90])[CH3:89])=[O:86])[CH:82]=[CH:83][C:74]=2[C@@H:65]([O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[CH2:64][N:56]([CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][CH2:46][CH2:45][C:42]2[CH:41]=[CH:40][C:10]([NH:13][C:14]([NH:16][CH2:17][C:18]3[C:19]([NH:31][CH:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[C:20]4[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:21]4=[N:22][C:23]=3[CH2:24][CH3:25])=[O:15])=[CH:9][CH:43]=2)[C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[N:79]=1)=[O:94])([CH3:97])([CH3:98])[CH3:99]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)Nc1ccc(C#CCCCBr)cc1
Reactant: CC(C)(C)OC(=O)Oc1ccc2c([C@H](CN(CCCCCCOCCCCc3ccc(N)cc3)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)ccc(OC(=O)OC(C)(C)C)c2n1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)Nc1ccc(CCCCOCCCCCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OC(=O)OC(C)(C)C)c3nc(OC(=O)OC(C)(C)C)ccc23)C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared in a manner analogous to that described for Intermediate 35, using Intermediate 42 in place of Intermediate 24. ES/MS calcd. for C65H99N8O12Si+ 1211.7. found m/z=1211.6 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([O:20]CC)=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+:24]>C(O)C>[CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([O-:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:3])[CH3:4].[Na+:24]
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@H](COCC(C)C)CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)[O-]
Yield: 69.9 %

Procedure:
Crude ethyl (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (7.82 g) synthesized according to the process (acid chloride method) similar to that described in Patent reference 1 was dissolved in ethanol (24 mL). While the solution was cooled with ice and stirred, 1 mol/L aqueous solution of sodium hydroxide (23.55 mL) was dropped. After the solution was stirred for 1.5 hours while the temperature was kept, the solvent was distilled off under reduced pressure. Water (39 mL) was added to the residue, and the obtained solution was washed with two portions of ethyl acetate (39 mL), and then water was distilled off under reduced pressure. Acetone (157 mL) was added to the residue, and the solution was stirred overnight at room temperature. The precipitated crystalline product was collected by filtration, washed with a mixture of 3% water-acetone (30 mL), washed again with acetone (30 mL), and dried in air to obtain white solid sodium (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (5.36 g, 69.9%). The NMR data of the solid product were the same as those in Example 9.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][CH:7]1[CH2:11][O:10]C(C)(C)[O:8]1)[CH3:2].Cl>O1CCCC1>[CH2:1]([C:3]1[CH:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][CH:7]([OH:8])[CH2:11][OH:10])[CH3:2]
Reactant: CCCCCCCCCCCCCCc1ccc(OCC2COC(C)(C)O2)c(CC)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1ccc(OCC(O)CO)c(CC)c1
Yield: 85.8 %

Procedure:
A mixture of 15.55 g of 4-[(2-ethyl-4-tetradecylphenoxy)methyl]-2,2-dimethyl-1,3-dioxolane, 10 ml of 5% hydrochloric acid and 300 ml of tetrahydrofuran was heated at reflux for 4 hours, then cooled and 1/2 of the solvent evaporated at reduced pressure. The remainder was diluted with ethyl acetate, washed with aqueous sodium bicarbonate, dried and the solvents evaporated. The residue was chromatographed on silica gel, eluting first with hexane:ethyl acetate (8:1), then (4:1), giving 12.1 g of the desired compound, mp 55°-56° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@@H:14]([CH2:38][C:39]([NH:41][C:42]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[C:15]([N:17]([C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)=[O:16]>>[CH2:32]([O:31][CH:30]([O:34][CH2:35][CH3:36])[C@@H:29]([N:17]([CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[C:15](=[O:16])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH2:38][C:39](=[O:40])[NH:41][C:42]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[CH3:37])[CH3:33]
Reactant: CCNC(=O)NN(C)CC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 41 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(naphthalen-1-ylmethyl)-N4-tritylsuccinamide (Compound IV-19) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: C([NH:8][C:9]1[C:18]([F:19])=[C:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[C:16]([F:27])=[C:15]2[C:10]=1[C:11](=[O:34])[C:12]([C:31]([OH:33])=[O:32])=[CH:13][N:14]2[CH:28]1[CH2:30][CH2:29]1)C1C=CC=CC=1.C(O)(=O)C>[C].[Pd].C(O)C>[NH2:8][C:9]1[C:18]([F:19])=[C:17]([N:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)[C:16]([F:27])=[C:15]2[C:10]=1[C:11](=[O:34])[C:12]([C:31]([OH:33])=[O:32])=[CH:13][N:14]2[CH:28]1[CH2:30][CH2:29]1
Reactant: CN1CCN(c2c(F)c(NCc3ccccc3)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
A mixture of 5-benzylamino-1-cyclopropyl-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (700 mg), 5% palladium-carbon (0.2 g), acetic acid (10 ml), and ethanol (15 ml) was stirred at room temperature for 30 minutes under a hydrogen stream. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. After addition of water to the residue, the mixture was adjusted to pH 8 with aqueous ammonia. The resulting crystals were filtered to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (510 mg), m.p. 254°-255° C.
Reaction SMILES: Cl.C([N:9]1[C:13]([CH2:14][CH:15]=[C:16]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][N:11]=[CH:10]1)C1C=CC=CC=1>C(O)C>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][C:13]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:28][CH:27]=1)#[N:30]
Reactant: N#Cc1ccc(C(=CCc2cncn2Cc2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(C(CCc2c[nH]cn2)c2ccccc2)cc1

Procedure:
1-benzyl-5-[3-(4-cyanophenyl)-3-phenyl-2-propenyl]-1H-imidazole hydrochloride is hydrogenated in ethanol using 10% Pd/C as a catalyst.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:29])[C@@H:11]([NH:19][C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:22][CH2:21]2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]([C:30]2[N:34](C3CCCCO3)[N:33]=[CH:32][CH:31]=2)=[CH:5][N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:29])[C@@H:11]([NH:19][C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:21][CH2:22]2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][C:6]([C:30]2[NH:34][N:33]=[CH:32][CH:31]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(-c2ccnn2C2CCCCO2)cc1NC(=O)[C@H](Cc1ccccc1)NC1(c2ccccn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(-c2ccn[nH]2)cc1NC(=O)[C@H](Cc1ccccc1)NC1(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a 20 ml vial was added (2S)—N-(2-methoxy-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)-3-phenyl-2-(1-(pyridin-2-yl)cyclopropylamino)propanamide 14.1.D (200 mg, 0.37 mmole), 8 ml of DCM and 2 ml of TFA. The reaction was stirred at room temperature for 2 hours then refluxed for 2 seconds at which time the solvent was removed with a stream of nitrogen. The crude was purified by reverse phase preparative HPLC to give (2S)—N-(2-methoxy-5-(1H-pyrazol-5-yl)pyridin-3-yl)-3-phenyl-2-(1-(pyridin-2-yl)cyclopropylamino)propanamide 14.1. (74 mg, 44% yield) LCMS ESI (pos.) m/e: 455.2 (M+1): 1H NMR (400 MHz, MeOH-d) δ ppm 8.59 (d, J=5.48 Hz, 1H), 8.56 (d, J=2.35 Hz, 1H,) 8.28 (d, J=2.35 Hz, 1H), 8.03-8.08 (m, 1H), 7.71 (d, J=2.35 Hz, 1H), 7.53-7.57 (m, 1H), 7.36 (d, J=8.22 Hz, 1H), 7.23-7.32 (m, 5H), 6.61 (d, J=2.35 Hz, 1H), 4.33 (t, J=7.63 Hz, 1H), 3.89 (s, 3H), 3.20 (d, J=7.83 Hz, 2H), 1.62-1.70 (m, 2H), 1.50-1.57 (m, 1H), 1.32 (ddd, J=10.17, 4.11, 2.15 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([NH:12][NH2:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[NH:14]1[C:18]2[N:19]=[CH:20][CH:21]=[C:22]([C:23](O)=O)[C:17]=2[CH:16]=[CH:15]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:11][C:23]([C:22]3[CH:21]=[CH:20][N:19]=[C:18]4[NH:14][CH:15]=[CH:16][C:17]=34)=[N:13][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccnc2[nH]ccc12
Reactant: NNC(=O)CCc1cccc(F)c1
Product: Fc1cccc(CCc2nnc(-c3ccnc4[nH]ccc34)o2)c1
Yield: 40 %

Procedure:
In the same manner as in Example 14 and using 3-(3-fluorophenyl)propanohydrazide instead of 1H-benzotriazole-5-carbohydrazide and 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 40%) was obtained as pale-yellow crystals.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH:3]([CH3:5])[CH3:4].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:30]([O:34][C:35](=[O:60])[NH:36][CH2:37][CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:48](=[NH:51])[NH:49]O)[CH:46]=2)[NH:41][C:40]=1[C:52]1[CH:57]=[C:56]([CH3:58])[CH:55]=[C:54]([CH3:59])[CH:53]=1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:60])[NH:36][CH2:37][CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:48]3[N:51]=[C:1]([CH2:2][CH:3]([CH3:5])[CH3:4])[O:7][N:49]=3)[CH:46]=2)[NH:41][C:40]=1[C:52]1[CH:53]=[C:54]([CH3:59])[CH:55]=[C:56]([CH3:58])[CH:57]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=N)NO)cc3c2CCNC(=O)OC(C)(C)C)c1
Reactant: CC(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1cc(C)cc(-c2[nH]c3ccc(-c4noc(CC(C)C)n4)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of isovaleric acid (0.025 mL in 4 mL methylene chloride) was added 1-hydroxybenzotriazole (37.8 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (43.6 mg) and the reagents allowed to mix for 30 minutes. At this time a solution of {2-[2-(3,5-dimethylphenyl)-5-(N-hydroxycarbamimidoyl)-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester (81 mg in 3 mL methylene chloride) was added and the reaction stirred at room temperature. After 2 hours, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride: methanol, 96:4) to give the title compound (81 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([N:20]1[CH2:38][CH2:37][CH2:36][C@H:21]1[C:22]([NH:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:32])[NH2:31])=[O:23])=[O:19])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C(OC2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.[C:62]([O:66][C:67]([NH:69][C@H:70]([C:74](O)=[O:75])[C@@H:71]([CH3:73])[OH:72])=[O:68])([CH3:65])([CH3:64])[CH3:63]>O.O1CCOCC1>[C:62]([O:66][C:67]([NH:69][C@H:70]([C:74]([NH:17][C@H:16]([C:18]([N:20]1[CH2:38][CH2:37][CH2:36][C@H:21]1[C:22]([NH:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:31])[NH2:32])=[O:23])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:75])[C@@H:71]([CH3:73])[OH:72])=[O:68])([CH3:64])([CH3:65])[CH3:63]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Fc1c(F)c(F)c(Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O

Procedure:
2.18 g (4.1 mmol) of Nε -benzyloxycarbonyl-lysyl-prolyl-arginine IV in 30 ml of water are added, under stirring, to a solution of 2.10 g (5.3 mmol) of pentafluorophenyl ether of tert.butyloxycarbonyl-threonine in 70 ml of dioxane. Then the reaction mixture is treated following the procedure described for the synthesis of compound III. The yield of the desired product--tert.butyloxycarbonyl-threonyl-Nε -benzyloxycarbonyl-lysyl-prolyl-arginine is 2.65 g (188%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:34][CH2:33]1)[CH3:19]>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:35]2[CH2:36][CH2:37][CH2:38][N:32]([C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:33][CH2:34]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(C2C=NN=N2)cc1C(=O)O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(C5C=NN=N5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-(4H-triazol-4-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give, after chromatography on silica gel eluting sequentially with 10% methanol/ethyl acetate and then 50% methanol/ethyl acetate, the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[C:13]([O-:18])(=[O:17])[C:14]([CH3:16])=[CH2:15].[K+].[I-].[K+].C1(C=CC(O)=CC=1)O>CN(C)C=O>[C:13]([O:18][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)C(=O)[O-]
Reactant: ClCCn1ccc2ccccc21
Agent: Oc1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCn1ccc2ccccc21
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 78.9 %

Procedure:
Subsequently, 1-(2-chloroethyl)indole (15.4 g), potassium methacrylate (21.3 g), potassium iodide (7.1 g), N,N-dimethylformamide (40 ml), and a small amount of hydroquinone were placed in a 200-ml flask equipped with a stirrer and a condenser tube. The mixture was heated to 100° C. and stirred for 2.5 hours. After completion of reaction, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. This reaction mixture was purified further by silica gel column chromatography to obtain 1-(2-methacryloyloxyethyl) indole (15.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[C:29](I)[C:24]=4[S:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[C:29]([C:34]5[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=5)[C:24]=4[S:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: Nc1ncc(I)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cccnc2)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 120 °C
Yield: 82 %

Procedure:
To a 25 mL microwave reaction tube was charged 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-iodothieno[3,2-c]pyridin-4-amine (150 mg, 0.274 mmol), 3-pyridinylboronic acid (33.7 mg, 0.274 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (11.19 mg, 0.014 mmol), and sodium carbonate (58.1 mg, 0.548 mmol) followed by dioxane (5 mL), and water (1 mL). The reaction was heated at 120° C. for 30 min in microwave reactor. Ethyl acetate (20 mL) was added and the layers were separated. The organic layer was washed with brine, concentrated, and the residue purified by silica gel chromatography (0%-100% EtOAc in hexanes). Product came out at 100% EtOAc, the fractions with the product was combined, evaporated to dryness to afford the title compound as a light gray solid (112 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (d, J=2.0 Hz, 1H) 8.62 (dd, J=4.8, 1.3 Hz, 1H) 8.04-8.18 (m, 2H) 7.97 (s, 1H) 7.56 (dd, J=7.6, 4.8 Hz, 1H) 7.51 (s, 1H) 7.39 (s, 1H) 7.14-7.32 (m, 4H) 5.64 (br. s., 2H) 4.32 (t, J=8.3 Hz, 2H) 3.97 (s, 2H) 3.29 (t, 2H).