Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH:11]2[CH2:14][C:13]([O:17][CH3:18])([O:15][CH3:16])[CH2:12]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](O)([C:28]([F:31])([F:30])[F:29])=[O:27].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[C:1]([N:5]1[C:9]([NH:10][C:26](=[O:27])[C:28]([F:31])([F:30])[F:29])=[CH:8][C:7]([CH:11]2[CH2:12][C:13]([O:15][CH3:16])([O:17][CH3:18])[CH2:14]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC1(OC)CC(c2cc(N)n(C(C)(C)C)n2)C1
Reactant: O=C(O)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC1(OC)CC(c2cc(NC(=O)C(F)(F)F)n(C(C)(C)C)n2)C1
Reaction time: 72 h
Yield: 59.6 %

Procedure:
To a stirring solution of 2-tert-butyl-5-(3,3-dimethoxy-cyclobutyl)-2H-pyrazol-3-ylamine (5.0 g, 19.7 mmol) in EtOAc (40 mL) was added triethylamine (27 mL, 197 mmol), TFA (2.3 mL, 29.6 mmol), followed by a solution of 1-propanephosphonic acid cyclic anhydride (25 mL, 50 wt % sol. in EtOAc, 39.4 mmol). After 72 hr, the reaction was diluted with EtOAc and washed with aqueous NaOH (1 N). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of this material was accomplished by MPLC, using a Biotage® column (35 L), eluting with 25% EtOAc/hexanes. The product-containing fractions were collected and concentrated to yield the title compound (4.1 g, 60% yield) as a colorless oil. 400 MHz 1H NMR (CDCl3) d 8.00 (bs, 1H), 6.26 (s, 1H), 3.22 (dddd, J=8.7, 8.7, 8.7, 8.7, Hz, 1H), 3.18 (s, 3H), 3.15 (s, 3H), 2.61-2.55 (m, 2H), 2.25-2.19 (m, 2H), 1.59 (s, 9H). LRMS m/z (APCI+) 350 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1>N.CO.[Ni]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([CH2:11][NH2:12])[CH:3]=1
Reactant: N#Cc1cc(F)cc2[nH]ccc12
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cc(F)cc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of 226 (588 mg, 3.68 mmol) in 7N NH3 in MeOH (20 mL) was added Raney nickel (20 mg), and then the reaction was stirred under hydrogen (1 atm.) at RT overnight. The dark mixture was filtered and the filtrate was concentrated in vacuo to afford 500 mg (85%) of (6-fluoro-1H-indol-4-yl)methanamine (228) as white solid: MS (ESI) m/z=148.1 [M−16]+.
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[N:18]1)[N:10]=[CH:9][N:8](COC(=O)C(C)(C)C)[C:7]2=O>CO>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[N:18]1)[N:10]=[CH:9][N:8]=[CH:7]2
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCn1ccnn1
Agent: N
Solvent: CO
Product: COc1cc2cncnc2cc1OCCn1ccnn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
5.1 M Ammonia in methanol (30 ml) was added to a solution of 6-methoxy-3-((pivaloyloxy)methyl)-7-(2-(1,2,3-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (1.4 g, 3.5 mmol) in a solution of methanol (30 ml). After stirring overnight at ambient temperature, the volatiles were removed by evaporation and the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinazoline (946 mg, 92%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[O:12]1CCC[CH2:13]1>B>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][CH2:10][NH2:11])=[C:2]([O:12][CH3:13])[CH:7]=1
Reactant: N#CCc1ccc(Cl)cc1Br
Reactant: C1CCOC1
Agent: B
Product: COc1cc(Cl)ccc1CCN

Procedure:
A portion of 2-(2-bromo-4-chlorophenyl)acetonitrile (7.1 g; 39.1 mmol) was directly dissolved in borane solution (78.2 mL of a 1.0 M solution in tetrahydrofuran; 78.2 mmol), and the resulting solution was stirred and heated to reflux. After refluxing for a total of 90 minutes, the heat was removed and the solution was allowed to cool for a few minutes, and then 16 mL of methanol was carefully added to quench the solution. The resulting solution was again heated to reflux for 30 minutes. The solvent was then evaporated, and the residue was partitioned between 200 mL of 1M HCl (aq.) and 200 mL ether. The aqueous layer was filtered to remove a small amount of suspended insoluble material, and the pH of the filtrate was adjusted to pH>12 by the addition of 42% NaOH (aq.). The filtrate was then extracted with 200 mL dichloromethane. The organic layer was dried over sodium sulfate and evaporated to give 3.89 g of 2-(4-chloro-2-methoxyphenyl)ethanamine as a colorless liquid. MS (apci, pos) m/z=186.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[N:2]1.[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][C:43](O)=[O:44])=[O:36])([CH3:33])([CH3:32])[CH3:31].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[C:43](=[O:44])[CH2:42][CH:38]2[CH2:39][CH2:40][CH2:41][N:37]2[C:35]([O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:36])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC1CC(=O)O
Reactant: COc1ccc(-c2ccc(CNCCCNc3nsc4ccccc34)cc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(CN(CCCNc3nsc4ccccc34)C(=O)CC3CCCN3C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
N1-(Benzo[d]isothiazol-3-yl)-N3-((4′-methoxybiphenyl-4-yl)methyl)propane-1,3-diamine (100 mg, 0.25 mmol), 2-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (68 mg, 0.34 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarboduimide hydrochloride (58 mg, 0.30 mmol) were dissolved in anhydrous methylene chloride (10 mL). Diisopropylethylamine (52 μL, mmol) added to the mixture. The reaction was allowed to stir overnight at room temperature. The solution was washed with water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 3:1 hexanes:ethyl acetate yielded tert-butyl 2-(2-((3-(benzo[d]isothiazol-3-ylamino)propyl)((4′-methoxybiphenyl-4-yl)methyl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate as a solid (30 mg). 1H NMR (300 MHz, CDCl3): 7.90-7.95 (m, 1H), 7.75-7.85 (m, 1H), 7.35-7.55 (m, 6H), 7.19-7.25 (m, 2H), 6.95-7.00 m, 2H), 4.90-5.00 (m, 1H), 4.55-4.65 (m, 2H), 4.19-4.25 (m, 1H), 3.85 (s, 3H), 3.55-3.65 (m, 2H), 3.30-3.35 (m, 2H), 3.10-3.19 (m, 1H), 2.35-2.45 (m, 1H), 2.05-2.15 (m, 1H), 1.80-1.90 (m, 4H), 1.50 ppm (s, 9H). MW=615 confirmed by LC-MS, tr=5.12 min (Method B) MH+=614-616.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.Cl[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][O:28][C:27]1=[O:31].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(O)CCC>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][O:28][C:27]4=[O:31])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1O2
Reactant: O=C1OCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Cl)ccc3Oc3ccccc32)CC1

Procedure:
8.5 G. of 1-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine are stirred at reflux for 4 hours together with 8.1 g. of 3-(2-chloro-ethyl)-2-oxazolidinone, 2.95 g. of sodium carbonate and 0.4 g. of sodium iodide in 50 ml. of butanol. Then, the solvent is evaporated under reduced pressure and the residue partitioned between water and chloroform. The organic phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is recrystallized from methanol, and there is obtained 3-[2-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone having a melting point of 159°-160° C. The maleate, prepared in acetone, melts at 175°-177° C. (with decomposition). The dihydrochloride hydrate, prepared in ethanol, melts at 179°-181° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([O-:14])=[O:13]>CN(C=O)C.C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)[N:3]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Nc2nc(Cl)nc3nc[nH]c23)cc1

Procedure:
1.9 g (10 mmol) of 2,6-dichloro-purine are stirred in 40 ml of DMF/n-butanol (1:3) with 4.1 g (30 mmol) of 4-nitro-aniline at 130° C. for 24 h and the crystal mass which precipitates out on cooling is filtered off and dried in vacuo. 2-Chloro-6-(4-nitro-phenyl-amino)-purine is obtained; m.p.>270° C.; FAB-MS: (M+H)+=291; Rf=0.6 (CH2Cl2:methanol=9:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:15]1[C:23]2[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=2[N:17]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH:16]=1.[C:31]([C:33](=[CH:37][CH:38]1[CH2:40][CH2:39]1)[C:34](O)=[O:35])#[N:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:24][C:22]1[C:23]2[C:15]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[CH:7][C:2]=3[F:1])=[CH:16][N:17]([CH2:25][CH:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:34]([C:33](=[CH:37][CH:38]3[CH2:40][CH2:39]3)[C:31]#[N:32])=[O:35])[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)cn2CC1CCCN1
Reactant: N#CC(=CC1CC1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CC(=CC1CC1)C(=O)N1CCCC1Cn1cc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.3 %

Procedure:
To a mixture of 5-(2-fluoro-4-phenoxy-phenyl)-7-pyrrolidin-2-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (100 mg, 0.25 mmol, 1.0 eq), 2-cyano-3-cyclopropyl-acrylic acid (42 mg, 0.3 mmol, 1.2 eq) and DIEA (97 mg, 0.75 mmol, 3.0 eq) in 10 ml of DCM was added HATU (145 mg, 0.38 mmol, 1.5 eq). The mixture was stirred for 4 h at RT under N2. LCMS showed the reaction was completed. The reaction mixture was concentrated and purified by Pre-TLC to provide 71 mg (54%) of the title compound. LCMS: m/z 523.2 (M+H)+. 1HNMR (400 MHz, DMSO-d6): δ 0.866˜0.920 (m, 2H), 1.177˜1.194 (m, 2H), 1.569 (m, 1H), 1.721 (m, 2H), 1.883 (m, 2H), 3.200 (m, 2H), 3.511 (m, 1H), 4.360˜4.475 (m, 2H), 6.125 (m, 2H), 6.642˜6.664 (m, 1H), 6.898˜6.920 (m, 1H), 6.977˜7.010 (m, 1H), 7.150˜7.232 (m, 4), 7.371˜7.471 (m, 3H) and 8.131 (m, 1H)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:27]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1cccc(Br)c1
Yield: 97.7 %

Procedure:
0.5 g (0.00216 mol) of 1-benzyl-4-hydroxypiperidine and 0.64 ml (0.0046 mol) of triethylamine were dissolved in 20 ml of toluene and treated with 0.37 ml (0.0027 mol) of 3-bromo-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.79 g (98%) of 1-benzyl-piperidin-4-yl 3-bromo-benzoate was obtained as a colorless oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[S:31][C:30]([Mg]Br)=[CH:29][CH:28]=1>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:30]3[S:31][C:27]([Cl:26])=[CH:28][CH:29]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Clc1ccc([Mg]Br)s1
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)s1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 0.5 mL THF and 2.0 mL 0.25M 5-chloro-2-thienylmagnesium bromide. Yield: 56 mg of a white solid. LC-MSD, m/z for C20H12BrClN2O2S [M+H]+=458.9, 460.9, 462.9; HPLC retention time: 2.5 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][CH:24]=1
Reactant: Clc1ccc(Br)cc1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: Cc1c(C)c(N2CCN(c3ccc(Cl)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 26 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (274 mg, 1.00 mmol) synthesized in Reference example 61 and 1-bromo-4-chlorobenzene (287 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 23 to obtain the title compound 100 mg (yield 26%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10]([NH:18][C:19]1[CH:24]=[CH:23][NH:22][C:21](=[O:25])[N:20]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:10]([NH:18][C:19]1[CH:24]=[CH:23][N:22]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:21](=[O:25])[N:20]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc(NC(=O)c2ccccc2)nc1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
tert-Butyl bromoacetate (24 ml; 0.15 mol) is slowly added dropwise, at room temperature, to a suspension of N4 -benzoylcytosine (21.5 g; 0.1 mol) and potassium carbonate 13.8 g; 0.1 mol) in anhydrous N,N-dimethylformamide (2.15 l). The heterogeneous mixture is stirred vigorously at room temperature for 20 h and insoluble starting material is subsequently filtered off with suction; the filtrate is concentrated in vacuo and the residue is subsequently distilled repeatedly with toluene and then taken up in chloroform (1.0 l); it is then extracted once by shaking with water (0.3 l), and the phases are swiftly separated. The organic phase is filtered once more and concentrated. Yield: 15.23.g (46%).
Reaction SMILES: C1[C@@H](C(NCC(N[C@H](C([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=O)CCCN=C(N)N)=O)=O)NC(=O)C1.C(O)(=O)C>C(O)C(N)(CO)CO.Cl>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([NH2:24])=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: NC(N)=NCCC[C@H](NC(=O)CNC(=O)[C@@H]1CCC(=O)N1)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CC(=O)O
Product: Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h

Procedure:
An inhibitor sample is dissolved in a 0.05 M Tris-hydrochloric acid buffer solution (pH=8.8) to make the total volume to 400 μl. To this solution, 50 μl of a 1 mM S-2444 solution is added and the mixture is incubated at a temperature of 37° C. for 5 minutes in a constant temperature bath. Then, 50 μl of a 500 unit/ml human urokinase is added and the mixture is incubated at a temperature of 37° C. for 5 minutes. Thereafter, 50 μl of 50% acetic acid is added to terminate the reaction. The absorbance of the p-nitroaniline formed in the reaction mixture is measured at 405 nm. Thus, the concentration I50 (μmol) of the inhibitor sample, at which the absorbance is one half (i.e., 1/2) of that obtained in the absence of the inhibitor sample, is determined.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:17]=[CH:16]4)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:25]1[CH2:24][CH2:23][CH:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[C:11]([C:9]4[NH:10][C:6]5[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=5[CH:8]=4)[CH:12]=[CH:13][CH:14]=3)[N:19]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(OC5CCNCC5)nc34)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a solution of tert-butyl 4-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)oxy)piperidine-1-carboxylate (0.103 g, 0.22 mmol) in DCM (3.0 mL) at 0° C. was added TFA (0.5 mL, 6.73 mmol). The reaction was stirred at 0° C. for 1 h, then at RT for 40 min. The reaction mixture was then concentrated, the residue was dissolved in DCM, washed with a saturated aq. solution of NaHCO3, dried over MgSO4, filtered and concentrated. The residue was dissolved in DMSO (2.0 mL) and purified by rpHPLC (Silicycle Silichrome XT C18 column; 30×150 mm, 5 μm, 5-95% 0.1% TFA/ACN in 0.1% TFA/water by volume over 10 min.), then dried in a Genevac Series II Evaporator to afford 2-(2-(piperidin-4-yloxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (48.7 mg, 0.094 mmol, 32.4% yield) as an amorphous orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.64 (br. s., 1H), 8.67 (br. s., 1H), 8.47 (br. s., 1H), 8.30 (d, J=9.0 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 6.95 (br. s., 1H), 5.37-5.48 (m, 1H), 3.34-3.50 (m, 4H), 3.18-3.31 (m, 2H), 2.88 (t, J=6.8 Hz, 2H), 2.36 (d, J=14.3 Hz, 2H), 1.87-2.02 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ ppm −74.36 (s, 3F). m/z (ESI, +ve ion) 363.0 (M+H)+.
Reaction SMILES: N[C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BrH:13].N([O-])=O.[Na+]>O>[C:4]1([CH2:3][C@@H:2]([Br:13])[C:10]([OH:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](Br)Cc1ccccc1
Temperature: -5 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
Mix D-phenylalanine (186.4g, 1.128mol) and 49% hydrobromic acid (372.8g), cool to -5° C. and add, by dropwise addition, a solution of sodium nitrite (77.9g) in water (565mL) over a period of about 1 hour (vigorous gas evolution). Stir at -5° C. to 0° C. for 4 hours, extract into ethyl ether (3×1L), dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (5% acetic aci/95% methylene chloride) and distillation to give 3-phenyl-2(R)-bromopropionic acid (112g, 43%); bp 128°-135° C. @0.25 torr.
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[N:13]=[N:14][N:15]([C:18]4[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=4)[C:16]=3[CH3:17])[CH:8]=2)[C:3]1=[O:25].[H][H]>[C].[Pd].C(O)C>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[N:13]=[N:14][N:15]([C:18]4[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=4)[C:16]=3[CH3:17])[CH:8]=2)[C:3]1=[O:25]
Reactant: Cc1c(-c2ccc3c(=O)n(C)ccc3c2)nnn1-c1cccnc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(-c2ccc3c(c2)CCN(C)C3=O)nnn1-c1cccnc1F
Yield: 19.9 %

Procedure:
20 mg of palladium carbon was added to 10 ml solution of ethanol with 5 mg of 4-(2-methyl-1-oxo-isoquinoline-6-yl)-1-(2-fluoropyridine-3-yl)-5-methyl-1H-[1,2,3]triazole, and hydrogen was added under 4 atm of hydrogen atomosphere. 8 hours later, the reaction solution was filtered, and after distilling out the solvents of the filtrate, the residues were separated and purified by preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 1 mg of the above compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH2:11][C:12]#[N:13])[CH:5]=[CH:4][N:3]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH2:11][C:12]#[N:13])[CH:5]=[CH:4][N:3]=2)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#CCc1ccnc(Cl)c1[N+](=O)[O-]
Reactant: c1ccc(CN2CCNCC2)cc1
Product: N#CCc1ccnc(N2CCN(Cc3ccccc3)CC2)c1[N+](=O)[O-]

Procedure:
A solution of 15 g of (2-chloro-3-nitropyridin-4-yl)acetonitrile and 1.1 equivalents of N-benzyl-piperazine is heated for 10 minutes, at 80° C., under a stream of argon, and then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane/methanol: 100/0 to 95/5) enables the expected product to be isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH2:13][OH:14])[C:9]=1[CH3:15].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[C:9]=1[CH3:15]
Reactant: Cc1c(CO)c[nH]c1-c1ccccc1F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: Cc1c(C=O)c[nH]c1-c1ccccc1F

Procedure:
By a similar operation as in Reference Example 15 and using [5-(2-fluorophenyl)-4-methyl-1H-pyrrol-3-yl]methanol (1.17 g), tetra-n-propylammonium perruthenate (101 mg), N-methylmorpholine N-oxide (1.01 g) and molecular sieves 4 A powder (572 mg), the title compound was obtained as pale-pink crystals (yield 0.67 g, 58%).
Reaction SMILES: [CH3:1][C:2]([CH2:13][CH2:14][CH2:15][CH:16]([CH3:28])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12].Cl.O>CO>[CH3:1][C:2]1([CH2:13][CH2:14][CH2:15][CH:16]([CH3:28])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:3][CH2:4][C:5]2[C:6](=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=2)[O:12]1
Reactant: CC(=CCc1ccc(O)cc1O)CCCC(C)CCCC(C)CCCC(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)CCCC(C)CCCC(C)CCCC1(C)CCc2ccc(O)cc2O1
Yield: 70 %

Procedure:
A solution of 4-(3,7,11,15-tetramethyl-2-hexadecenyl)-1,3-benzenediol (870 mg; 2.24 mmole) and conc. hydrochloric acid (2.0 ml) in methanol (15 ml) was heated under reflux for 4 hours, then the reaction solution was poured into 70 ml of water and was extracted twice with isopropyl ether (50 ml). The extract was washed with 100 ml of water (twice) and 100 ml of saturated aqueous solution of sodium chloride (once), followed by drying it over anhydrous magnesium sulfate, distilling off the solvent and subjecting the resultant residue to silica gel column chromatography to thus obtain 610 mg of the title compound from the fractions eluted with hexane-ethyl acetate (10:1). Yield=70%.