Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[I:30][C:31]1[CH:32]=[C:33]([OH:40])[CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[CH:36]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:40][C:33]2[CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[CH:36]=[C:31]([I:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: O=[N+]([O-])c1cc(O)cc(I)c1
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc([N+](=O)[O-])c2)c1CCC(=O)OCC
Yield: 73.3 %

Procedure:
A similar procedure as described in Example 12, step 7 was used, starting from 4-[3-(6-bromo-hexyl)-2-(ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (9.39 g, 19.92 mmol) and 3-iodo-5-nitro-phenol (4.8 g, 18.11 mmol) to afford 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-nitro-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (8.7 g, 73%) as a light yellow oil: ES(+)-HRMS m/e calculated for C29H38INO8 (M+H)+ 656.1715, found 656.1721.
Reaction SMILES: [C-:1]#[N:2].[Na+].CC1C=CC(S(O[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([NH2:33])=[O:32])[CH:26]=2)(=O)=O)=CC=1>O.CCO>[C:1]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]([C:31]([NH2:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)#[N:2]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCCCOc2cccc(C(N)=O)c2)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCCCCCCCCCOc1cccc(C(N)=O)c1
Temperature: 75 °C
Reaction time: 48 h
Yield: 21 %

Procedure:
Sodium cyanide (60 mg, 1.22 mmol, 1.3 equiv.) was added to a solution of 9-[3-(aminocarbonyl)phenoxy]nonyl 4-methylbenzenesulfonate (407 mg, 0.94 mmol, 1 equiv.) in water (10 ml) and 95% EtOH (8 ml), and the reaction mixture was stirred at 75° C. for 2 days. After cooling at r.t., the mixture was diluted with water (10 ml) and extracted with CH2Cl2 (3×10 ml). The combined organic extracts were dried (MgSO4) and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography on silica eluting with EtOAc/hexane (50%), to give the desired compound as white solid (57 mg, 21%), mp 96-97° C. HPLC-MS (method 1): m/z 289 [M+H]+, Rt=4.16 min.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]([NH2:22])=[O:21].F[C:24]1[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[CH:35]=[CH:34][C:25]=1[CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC#N>[NH2:1][C:2]1[N:6]([C:24]2[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[CH:35]=[CH:34][C:25]=2[CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C:3]=1[C:20]([NH2:22])=[O:21]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: O=[N+]([O-])c1ccc(COC2CCCCO2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2cc([N+](=O)[O-])ccc2COC2CCCCO2)c1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (27.6 mg, 0.1 mmol) in DMF (3 mL) and CH3CN (5 mL) was added 2-(2-fluoro-4-nitrobenzyloxy)-tetrahydro-2H-pyran (25.5 mg, 0.1 mmol) and K2CO3 (27.6 mg, 0.2 mmol). After stirring at 80° C. under N2 for 16 hr, the mixture was concentrated and recrystallized with PE/EA to afford 40 mg (80%) of 5-amino-1-(5-nitro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide as a yellow solid. MS (ESI) m/e [M+1]+ 512.2.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@H:10]([CH3:25])[NH:11][C:12](=[O:24])[C@H:13]([CH3:23])[N:14](C(OC(C)(C)C)=O)[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9](=[O:26])[C@H:10]([CH3:25])[NH:11][C:12](=[O:24])[C@H:13]([CH3:23])[NH:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 17 g (0.0466 mole) of Boc-N-methyl-L-alanyl-L-alanine benzyl ester in 150 ml of dry dichloromethane, cooled at -10° C., was added 100 ml trifluoroacetic acid, which was previously cooled at -10° C. The reaction mixture was stirred for 16 hours at -5° C., then poured carefully with good stirring into a mixture of 177 g of sodium bicarbonate, ice, and 150 ml of dichloromethane. The organic layer was separated and the aqueous layer was further extracted with another 60 ml of dichloromethane. The combined organic layers were washed with 3×50 ml of saturated sodium bicarbonate solution, dried over mangesium sulfate, and evaporated to give 11.6 g (91% of theory) of crude product which was used in step 3 without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 4-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.97 min.; [M+H]+: 411.97 g/mol.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:12])[CH3:11])=[N:8][CH:9]=1.[CH2:13](Cl)[O:14][CH3:15]>CN(C=O)C>[CH3:13][O:14][CH2:15][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:12])[CH3:11])=[N:8][CH:9]=1
Reactant: COCCl
Reactant: CC(=O)c1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(C(C)=O)nc1
Reaction time: 1 h
Yield: 84.8 %

Procedure:
NaH was added to a solution of 1 g (7.29 mmol) 1-(5-hydroxy-pyridin-2-yl)-ethanone (Anichem) in 15 ml DMF at 0° C. After stirring this mixture for 1 h, 0.78 ml (8.75 mmol) MOMCl was added at 0° C. Then the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured on water and extracted 2 times with EtOAc. The combinded organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel (EtOAc, heptane) to yield 1.12 g of the pure title compound as an oil. LCMS (method L): tR=0.66 min, M+H=182.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.Cl.[CH3:19][N:20]([CH3:25])[CH2:21][C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH3:19][N:20]([CH3:25])[CH2:21][C:22]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)=[O:23]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)CN(C)C)C2
Yield: 85.6 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.3 g, 10 mmol) was dissolved in dimethylformamide (100 ml) while being cooled on ice. To the obtained mixture, a hydrochloric acid salt of N,N-dimethylglycine (1.45 g, 11 mmol), WSC.HCl (2.0 g, 11.0 mmol), and HOBT (1.4 g, 11.0 mmol) were added, and the resultant mixture was stirred at room temperature overnight. The reaction mixture was subjected to distillation under reduced pressure. The resultant residue was recrystallized from ethanol--hexane. As a result, 2.7 g of the title compound was obtained as pale yellow powdery crystals (77.0%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][CH2:48][CH:49]([OH:61])[CH2:50][N:51]1[CH2:60][CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:52]1[C:53]2[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:59][CH2:60][N:51]1[CH2:50][CH:49]([OH:61])[CH2:48][NH:47][C:17]([C:16]1[CH:15]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:22]=[CH:21][CH:20]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)O)c2)CC1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.3 %

Procedure:
The solution of 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (300 mg, 1.0 mmol) and HATU (381 mg, 1.0 mmol) in DCM (10 mL) was stirred at 25° C. for 30 min. Then 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (200 mg, 1.0 mmol) and DIPEA (259 mg, 2.00 mmol) was added and the resulting solution was stirred at 25° C. for 16 h. The solution was concentrated and the residue was purified by column chromatography to give the title product (140 mg, Yield 28.8%). LCMS (m/z): 495.2 (M+1).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][NH:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])/[CH:22]=[C:23](\[NH2:25])/[CH3:24])=[CH:16][C:15]=3[F:27])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:28](OCC)(OCC)(OCC)[CH3:29]>>[C:1]12([CH2:11][CH2:12][NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[C:21](=[O:26])[CH:22]=[C:23]([CH3:24])[N:25]=[C:28]4[CH3:29])=[CH:16][C:15]=3[F:27])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(C)(OCC)OCC
Reactant: C/C(N)=C/C(=O)Nc1ccc(NCCC23CC4CC(CC(C4)C2)C3)c(F)c1
Product: Cc1cc(=O)n(-c2ccc(NCCC34CC5CC(CC(C5)C3)C4)c(F)c2)c(C)n1
Temperature: 150 °C
Reaction time: 12 h
Yield: 3 %

Procedure:
A mixture of (Z)—N-(4-((2-(adamantan-1-yl)ethyl)amino)-3-fluorophenyl)-3-aminobut-2-enamide (0.31 g, 0.83 mmol) and triethyl orthoacetate (20 mL) was stirred at 150° C. for 12 h. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a red brown solid (10 mg, 3%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:20]1[CH:26]=[CH:25][C:23](N)=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.N([O-])=O.[Na+].[BrH:35]>O.[Cu]Br>[C:1]([C:20]1[CH:26]=[CH:25][C:23]([Br:35])=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: Nc1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Brc1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
25 parts by weight of 4-tritylaniline, 400 parts by weight of acetone, and 162 parts by weight of hydrobromic acid were put into a reaction vessel and stirred. While cooling the vessel in an ice bath, a solution of 7 parts by weight of sodium nitrite dissolved in 100 parts by weight of water was slowly added dropwise thereto. After the dropwise addition was complete, stirring was carried out for 30 minutes in an ice bath. Slowly added dropwise to this solution in an ice bath was a solution of 17.4 parts by weight of copper (I) bromide that had been dissolved in 31.5 parts by weight of hydrobromic acid. After the dropwise addition was complete, stirring was carried out at room temperature for 2 hours. After the reaction, a precipitate deposited in the reaction solution was collected by filtration, thus giving 25.8 parts by weight of 4-tritylbromobenzene (yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:27]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: O=C1CCc2cc(OCCCCCSc3ccc(Cl)c(Cl)c3)ccc2N1
Product: O=C1CCc2cc(OCCCCCS(=O)c3ccc(Cl)c(Cl)c3)ccc2N1

Procedure:
Prepared analogous to Example 123 from 6-[5-(3,4-dichlorophenyl-mercapto)-pentoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](NCC4C=CC=CN=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[CH3:100][O:101][C:102](=[O:111])[C:103]1[CH:108]=[CH:107][C:106]([CH2:109][NH2:110])=[CH:105][CH:104]=1>>[ClH:45].[CH3:100][O:101][C:102](=[O:111])[C:103]1[CH:108]=[CH:107][C:106]([CH2:109][NH:110][C:70]([NH:69][C@@H:66]2[CH2:67][CH2:68][N:64]([C:62]3[N:61]=[C:60]4[C:56]([N:57]=[CH:58][N:59]4[C@@H:80]4[CH2:84][C@H:83]([N:85]5[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]5)[C@@H:82]([OH:92])[C@H:81]4[OH:93])=[C:55]([NH:54][CH2:53][CH:52]([C:94]4[CH:95]=[CH:96][CH:97]=[CH:98][CH:99]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:63]=3)[CH2:65]2)=[O:71])=[CH:105][CH:104]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccc(C(=O)OC)cc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxcyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with 4-aminomethyl-benzoic acid methyl ester. MS (ES+) m/e 787.45 (MH+)
Reaction SMILES: OC(C(F)(F)F)=O.[OH:8][NH:9][C:10]([C@H:12]1[CH2:17][C@H:16]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH2:15][N:14]([CH3:25])[C@@H:13]1[C:26]([N:28]1[CH2:33][CH:32]=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])=[O:11].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[OH:8][NH:9][C:10]([CH:12]1[CH2:17][CH:16]([O:18][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[CH2:15][N:14]([CH3:25])[CH:13]1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])=[O:11]
Reactant: CN1C[C@@H](Oc2ccncc2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CC=C(c2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(Oc2ccncc2)CC(C(=O)NO)C1C(=O)N1CCC(c2ccccc2)CC1
Yield: 91.2 %

Procedure:
A mixture of (2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxamide TFA salt (4 mg, 0.00001 mol) in 1 mL of MeOH was hydrogenated in the presence of 5% Pd/BaSO4, under balloon pressure of hydrogen, for 2 h. After filtered off the catalyst, the filtration was concentrated to dry to yield The titled compound (4 mg, 100%). MS (ESI): (M+H)+=439.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)=[CH:5][CH:4]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:5][CH:4]=1
Reactant: C1CCNC1
Reactant: COc1ccc(C(=O)CCCCl)c2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CCCN2CCCC2)c2c1CCCC2
Temperature: 60 °C
Reaction time: 10 h
Yield: 81.9 %

Procedure:
A mixture of 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-4-chloro-1-butanone (4.0g), pyrrolidine (4.27g), potassium iodide (0.3g) and potassium carbonate (2.0g) in absolute N,N-dimethylformamide (30 ml) was stirred at 60° C. for 10 hours. The reaction mixture was filtered and then the filtrate was partitioned into water and ethyl acetate. The organic layer was extracted, washed with water and then dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate was evaporated in vacuo to give the residue. The residue was dissolved in ethyl ether. The ethyl ether solution was extracted with 1N hydrochloric acid. The aqueous layer was neutralized with ammonia water and then extracted with ethyl ether. The ethyl ether was dried over anhydrous magnesium sulfate. The solution was filtered and the filtrate was evaporated in vacuo to give 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-4-pyrrolidino-1-butanone (3.7 g; yield: 82%) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[CH3:28].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1CCCC1=O.O.[Cu]Cl>[CH3:16][O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)=[CH:23][C:22]=1[CH3:28]
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)CCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1C
Temperature: 120 °C
Yield: 50.7 %

Procedure:
A mixture of 3-benzyloxy-1-bromobenzene (14.53 g, 55.2 mmol), 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (10.72 g, 55.2 mmol) cesium carbonate (21.59 g, 66.3 mmol), and 2,2,6,6-tetramethyl-3,5-heptanedione (2.54 g, 13.8 mmol) in 1-methyl-2-pyrrolidinone (100 mL) is purged with N2, and then copper (I) chloride (2.73 g, 27.6 mmol) is added. The reaction mixture is heated to 120° C. for 18 hours under N2. The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using a gradient of 19/1 to 9/1 hexanes/ethyl acetate to afford about 10.54 g (51%) of the titled compound. Rf=0.53 (100% hexanes). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C24H24O4 376, found 377 (M+1, 100%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH2:11](I)[CH3:12]>CN(C)C=O.O>[CH2:11]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1)[CH3:12]
Reactant: CCI
Reactant: Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 16.6 g sodium hydride in 500 ml dry dimethylformamide (DMF) under nitrogen at 0° C. is added 90 g 5-hydroxy-2-methylpyridine at such a rate that the temperature remains between 0°-5° C. When gas evolution ceases, 73.8 ml ethyl iodide in 100 ml DMF is added dropwise. After stirring at room temperature overnight, the mixture is diluted with water and extracted with ether. The ether extracts are washed with brine, dried and concentrated. This oil is distilled to give 62.5 g of 5-ethoxy-2-methylpyridine, bp 89°-91° C. at 12 mm.
Reaction SMILES: [OH-].[K+].C([O:7][C:8](=[O:19])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][N:12]=1)(C)(C)C.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([C:34](=[O:36])[CH3:35])[CH:31]=[CH:32][CH:33]=2)[CH2:23][CH2:22]1>CCO.O>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([C:34](=[O:36])/[CH:35]=[CH:17]/[C:14]3[CH:15]=[CH:16][C:11](/[CH:10]=[CH:9]/[C:8]([OH:7])=[O:19])=[N:12][CH:13]=3)[CH:31]=[CH:32][CH:33]=2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Reactant: CC(=O)c1cccc(CN2CCN(C)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(Cc2cccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)c2)CC1
Temperature: 0 °C
Reaction time: 7 h
Yield: 47.4 %

Procedure:
1.7 M KOH (0.634 ml) was added dropwise to a stirred mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (see Example 11 STEP A-D, 250 mg, 1.078 mmol) and 1-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-ethanone (obtained as described in Preparation 14, 250 mg, 1.078 mmol) in EtOH (15 ml). The resulting solution was stirred at 0° C. for 7 h and then diluted with water and extracted with AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by chromatographic column (eluent: DCM/MeOH/NH4OH from 97:3:0.1 to 95:5:0.2) and the desired intermediate was dissolved in DCM (4 ml) and TFA (1 ml). The mixture was stirred at room temperature for 6 h and then the solvent was removed in vacuo to give 200 mg of (E)-3-(5-{(E)-3-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid as its tris-trifluoroacetate salt. The crude mixture was used in the next step without further purifications.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][N:12]=[CH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:32]([C:35]1[O:39][C:38]([C:40](Cl)=[O:41])=[CH:37][CH:36]=1)([O-:34])=[O:33]>C(OCC)(=O)C>[N+:32]([C:35]1[O:39][C:38]([C:40]([O:24][C:19]2[CH:18]=[CH:17][C:16]3[C:21](=[CH:22][CH:23]=[C:14]([CH:13]=[N:12][NH:11][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH:15]=3)[CH:20]=2)=[O:41])=[CH:37][CH:36]=1)([O-:34])=[O:33]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Reactant: O=C(NN=Cc1ccc2cc(O)ccc2c1)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NN=Cc1ccc2cc(OC(=O)c3ccc([N+](=O)[O-])o3)ccc2c1)OCc1ccccc1

Procedure:
To a solution of 3.2 g of 6-(benzyloxycarbonylaminoiminomethyl)-2-naphthol in 40 ml of ethyl acetate, was added 1.2 g of triethylamine. To the resulting solution, while cooling in ice and stirring, was added 5-nitrofuran-2-carboxylic acid chloride. Thereafter the mixture was stirred overnight at room temperature. The precipitate was collected by filtration and washed with water to obtain 4.4 g of 6-(benzyloxycarbonylaminoiminomethyl)-2-naphthyl 5-nitrofuran-2-carboxylate, m.p.: 109°-112° C.