Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH2:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:22])=[C:5]([C:18](OC)=[O:19])[C:6]([C:14](OC)=[O:15])=[N:7]2.O.[NH2:24][NH2:25]>C(O)C>[Br:1][C:2]1[C:3]2[C:4]([OH:22])=[C:5]3[C:18](=[O:19])[NH:25][NH:24][C:14](=[O:15])[C:6]3=[N:7][C:8]=2[CH:9]=[C:10]([CH2:12][CH3:13])[CH:11]=1
Reactant: NN
Reactant: CCc1cc(Br)c2c(O)c(C(=O)OC)c(C(=O)OC)nc2c1
Solvent: CCO
Solvent: O
Product: CCc1cc(Br)c2c(O)c3c(=O)[nH][nH]c(=O)c3nc2c1

Procedure:
To a mixture of dimethyl 5-bromo-7-ethyl-4-hydroxyquinoline-2,3-dicarboxylate (1.0 g, 2.7 mM,) in ethanol (25 mL) was added hydrazine hydrate (0.68 g, 14 mM). The resulting mixture was concentrated at 30° C. using a rotary evaporator and the residue was diluted with another portion of ethanol (25 mL) and similarly concentrated at 30° C. The residue was suspended in ethanol and filtered to separate the title compound (0.82 g, 82%) as a light yellow solid. Recrystallization of a portion of this material from dimethylsulfoxide/ethanol provided an analytical sample of the title compound as a light yellow crystalline solid, mp 335°-340° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([NH:27][C:28]([C:30]2[C:35](=[O:36])[N:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:33]=[CH:32][CH:31]=2)=[O:29])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)[S:13][C:6]=12.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.[NH:66]1[CH2:70][CH2:69][C@@H:68]([OH:71])[CH2:67]1.CCN(C(C)C)C(C)C>O.CN(C=O)C>[F:1][C:2]1[CH:26]=[C:25]([NH:27][C:28]([C:30]2[C:35](=[O:36])[N:34]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)[N:33]=[CH:32][CH:31]=2)=[O:29])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([N:66]4[CH2:70][CH2:69][C@@H:68]([OH:71])[CH2:67]4)=[O:20])=[CH:21][CH:22]=3)[S:13][C:6]=12
Reactant: O=C(O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)cc1
Reactant: O[C@@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CC[C@@H](O)C5)cc4)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Reaction time: 0.75 h
Yield: 55.4 %

Procedure:
A capped vial was charged with 4-(7-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzoic acid (0.100 g, 0.168 mmol), HOBT-H2O (0.103 g, 0.671 mmol), EDCI (0.129 g, 0.671 mmol), and DMF (2 mL). After stirring for 45 minutes, (R)-pyrrolidin-3-ol (0.0584 g, 0.671 mmol) and Hunig's base (0.175 ml, 1.01 mmol) were added. After stirring for 18 hours, water (20 mL) was added. The formed precipitate was isolated by filtration. After drying, (62 mg, 55%) of product was isolated as orange solid. LRMS (esi+) 666 m/z (M+1) detected. 1H NMR (CDCl3, 400 MHz) δ 11.84 (s, 1H), 8.47 (s, 1H), 8.39 (d, J=4 Hz, 1H), 8.22 (d, J=4 Hz, 1H), 7.97 (m, 1H), 7.76 (m, 3H), 7.62 (m, 4H), 7.39 (d, J=9 Hz, 1H), 7.26 (m, 3H), 6.52 (d, J=6 Hz, 1H), 4.50 (br s, 1H), 3.72 (m, 5H), 2.07 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20]C4CCCCO4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[O:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[CH:4][CH:3]=1>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[O:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[CH:37][CH:38]=1
Reactant: Cc1ccc(Oc2nc3c(c(=O)n(CCCOC4CCCCO4)c(=O)n3C)n2Cc2ccc(Cl)cc2)cn1
Agent: Cl
Product: Cc1ccc(Oc2nc3c(c(=O)n(CCCO)c(=O)n3C)n2Cc2ccc(Cl)cc2)cn1
Yield: 52.6 %

Procedure:
A solution of 7-(4-chlorobenzyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (79 mg, 0.146 mmol) in 1N ethanolic HCl (3 mL) was stirred at room temperature for 2 h. The mixture was concentrated to dryness to give a crude product, which was purified via preparative HPLC to give 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione (35 mg, 52.6% yield) as white solid. 1H-NMR (DMSO-d6) δ 8.69(s, 1H), 8.03-8.01(d, 1H), 7.59-7.57(d, 1H), 7.45(s, 4H), 5.45(s, 2H), 4.06-3.98(m, 2H), 3.45-3.42(t, 2H), 3.28(s, 3H), 2.59(s, 3H), 1.71-1.67(t, 2H). LCMS retention time 2.207 min; LCMS MH+ 456.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH2:9][C:10]([O:12][CH2:13]C)=[O:11])[N:3]=1.[Na].Cl.[CH3:17][OH:18]>>[NH2:1][C:2]1[CH:7]=[C:6]([O:18][CH3:17])[N:5]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[N:3]=1
Reactant: CCOC(=O)Cc1nc(N)cc(Cl)n1
Reactant: CO
Agent: Cl
Agent: [Na]
Product: COC(=O)Cc1nc(N)cc(OC)n1
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(4-amino-6-chloropyrimidin-2-yl)acetate (21.5 g) in methanol (200 ml) was added a solution of sodium metal (7.25 g) in methanol (130 ml) and the mixture was refluxed for 3.5 hours. The reaction mixture was cooled in an ice-salt bath and saturated with dry hydrogen chloride and then allowed to stand overnight at ambient temperature. The mixture was evaporated to dryness and the residue was dissolved in a mixture of ethyl acetate and a cold aqueous solution of sodium bicarbonate. The organic layer was separated out, washed with water, dried over anhydrous magnesium sulfate and and evaporated to give methyl 2-(4-amino-6-methoxypyrimidin-2-yl)acetate (14.2 g), mp 91°-94° C.
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:15]2[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2.C(N(CC)CC)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>O1CCCC1>[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:1][N:2]=[C:3]2[C:4]3[CH:5]=[CH:6][C:7]([O:18][CH3:19])=[CH:8][C:9]=3[C:10]3[C:15]2=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)-c1cc(OC)ccc1C2=NO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)-c1cc(OC)ccc1C2=NOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
3.8 g (0.015 mol) of 9-hydroxyimino-3,6-dimethoxyfluorene and 2.3 g (0.0225 mol) of triethylamine are suspended in 80 ml of tetrahydrofuran (THF) and, at 0° C., a solution of 3.1 g (0.0165 mol) of para-toluenesulfonic acid chloride in 20 ml of THF is added dropwise. After 4 hours, the ice-bath is removed and the reaction mixture is stirred overnight at room temperature. Then 40 ml of CH2Cl2 are added and the resulting ammonium salts are filtered off. The filtrate is washed with water and saturated NaCl, dried over magnesium sulfate and concentrated in a rotary evaporator. The resulting crude product is purified by flash chromatography on silica gel (eluant: petroleum ether/ethyl acetate 2:1). The fraction containing the main product is taken up in 100 ml of hot ethanol and the solution is filtered while hot. On cooling, the product precipitates and is filtered off and dried in vacua. 3.2 g (52%) of 9-(4-methylphenylsulfonyl-oxyimino)-3,6-dimethoxyfluorene are obtained in the form of yellow crystals having a melting point of 143-148° C. The UV spectrum (acetonitrile) of the substance shows absorption bands with a maximum at 314 nm (ε=21100) that extend to 450 nm. Elemental analysis: C22H19NO5S (409.6)
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:7][CH2:6][CH:5]=[CH:4][O:3]1.B.C1C[O:22]CC1.C([O-])(=O)C.[Na+].OO>C1COCC1.O.CCOC(C)=O>[OH:22][CH:5]1[CH2:4][O:3][C:2]([CH3:1])([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:7][CH2:6]1
Reactant: CC1(C(=O)OCc2ccccc2)CCC=CO1
Reactant: C1CCOC1
Agent: B
Agent: CC(=O)[O-]
Agent: OO
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C(=O)OCc2ccccc2)CCC(O)CO1
Reaction time: 4 h

Procedure:
To a solution of benzyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate (1.0 g, 3.44 mmol) in THF (10 mL) was added BH3.THF (2.07 mL, 2.07 mmol) dropwise in an ice/acetone bath in 10 min. The reaction mixture was stirred in the bath for 4 h. The reaction mixture was quenched by the addition of a solution of sodium acetate (0.283 g, 3.44 mmol) in water (3 mL). After being stirred for 10 min, H2O2 (0.3 mL, 4.89 mmol) was added. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc and washed with sat. NH4Cl, brine, and dried (MgSO4). The solvent was removed in vacuum to afford benzyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate.
Reaction SMILES: [I:1]Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[Cl:11])[NH2:7]>C(O)(=O)C>[Cl:11][C:10]1[C:4]([Cl:3])=[CH:5][C:6]([NH2:7])=[C:8]([I:1])[CH:9]=1
Reactant: ClI
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
Iodine monochloride (1.39 mL; 27.77 mmol) was added to a solution of 3,4-dichloroaniline (4.50 g; 27.77 mmol) in acetic acid (15 mL) and the resulting mixture was stirred for 30 minutes at room temperature. The solution was concentrated to dryness, neutralized with sodium bicarbonate and extracted with dichloromethane. The combined organic layers were washed with a saturated solution of sodium thiosulfate, dried and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to afford 3.46 g (43%) of the title compound as a brown solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[F:12][C@@H:13]1[CH:17]([O:18][CH3:19])[O:16][C@H:15]([CH2:20][OH:21])[C@H:14]1[OH:22].CO>CN(C)C=O>[F:12][C@H:13]1[C@H:14]([O:22][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([CH3:3])=[CH:5][CH:6]=2)[C@@H:15]([CH2:20][O:21][CH2:3][C:4]2[CH:11]=[CH:10][C:7]([CH3:8])=[CH:6][CH:5]=2)[O:16][CH:17]1[O:18][CH3:19]
Reactant: COC1O[C@H](CO)[C@@H](O)[C@@H]1F
Reactant: Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC1O[C@H](COCc2ccc(C)cc2)[C@@H](OCc2ccc(C)cc2)[C@@H]1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
In a nitrogen atmosphere, 0.44 g of sodium hydride and 2.03 g of 4-methylbenzyl bromide were added to a solution of 0.70 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol in 7.0 mL of N,N-dimethylformamide under cooling on ice, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, 2.5 mL of methanol was added to the reaction mixture to terminate the reaction, and ethyl acetate and hexane were then added thereto. The reaction mixture was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 60/40), so as to obtain 1.33 g of (3S,4R,5R)-3-fluoro-2-methoxy-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)oxolane in the form of a colorless oily product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:36]=[C:37](\[C:41]2[CH:46]=[CH:45][C:44]([S:47]([CH3:50])(=[O:49])=[O:48])=[CH:43][CH:42]=2)/[C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[CH:28]1(/[CH:36]=[C:37](\[C:41]2[CH:46]=[CH:45][C:44]([S:47]([CH3:50])(=[O:48])=[O:49])=[CH:43][CH:42]=2)/[C:38]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:39])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
A solution of triphenylphosphine (2.09 g, 8 mmol) in methylene chloride (25 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (1.42 g, 8 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-3-cyclooctyl-2-(4-(methanesulfonyl)-phenyl)-acrylic acid (1.345 g, 4 mmol) in methylene chloride (10 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (1.2 g, 12 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (100 mL) and a 1N aqueous hydrochloric acid solution (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 5/1 to 3/2 hexanes/ethyl acetate) afforded (E)-3-cyclooctyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-acrylamide (1.22 g, 73%) as an amorphous solid: EI-HRMS m/e calcd for C21H26N2O3S2 (M+) 418.1385, found 418.1385.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:31])[C@@H:13]2[CH2:17][C@@H:16]([NH:18][C:19](=[O:30])[C@H:20]([OH:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][NH:14]2)[CH:2]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])[CH2:41][CH:40]1[C:55](O)=[O:56])=[O:38])([CH3:35])([CH3:34])[CH3:33].N1C2C(=CC=CC=2)C=C(NC(=O)[C@@H]2C[C@@H](NC(=O)[C@H](O)CCC3C=CC=CC=3)CN2C(=O)[C@@H]2C[C@@H](NC(OC(C)(C)C)=O)CN2C(OC(C)(C)C)=O)C=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:31])[C@@H:13]2[CH2:17][C@@H:16]([NH:18][C:19](=[O:30])[C@H:20]([OH:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][N:14]2[C:55]([CH:40]2[CH2:41][N:42]([C:45]([O:47][CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[O:46])[CH2:43][CH2:44][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])=[O:56])[CH:2]=1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2cnc3ccccc3c2)C1)[C@H](O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1C(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1C(=O)N1C[C@H](NC(=O)[C@H](O)CCc2ccccc2)C[C@H]1C(=O)Nc1cnc2ccccc2c1

Procedure:
trans-4-((R)-2-hydroxy-4-phenybutyrylamino)-L-proline 3-quinolylamide (Compound D101 (H), 272 mg) and 1-tert-butoxycarbonyl-4-benzyloxycarbonylpiperazine-2-ylcarboxylic acid (A, 237 mg) were coupled using the same procedure of Compound D101 (P) to afford the title compound (171 mg) as a colorless glassy solid: mass spectrum (FAB+) m/e 765 (M+1).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)=[O:6])#[N:2].CS(O)(=O)=O>O1CCOCC1>[C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)=[O:6])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cccc(N4CCCCC4C(=O)NCC#N)c3)cc2)CC1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: N#CCNC(=O)C1CCCCN1c1cccc(-c2ccc(N3CCNCC3)cc2)c1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-[3′-(2-{[(cyanomethyl)amino]carbonyl}-1-piperidinyl)[1,1′-biphenyl]-4-yl]-1-piperazinecarboxylate (249 mg, 0.51 mmol) in dioxane (5 mL) was added methanesulfonic acid (0.1 mL, 1.5 mmol). The mixture was stirred overnight, then partitioned between EtOAc and 1 M NaOH. The organic phase was washed with brine and dried over MgSO4. Purification by flash chromatography (5% MeOH/dichloromethane with 0.5% NH4OH) gave N-(cyanomethyl)-1-[4′-(1-piperazinyl)[1,1′-biphenyl]-3-yl]-2-piperidinecarboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:25])[CH2:11][N:10]([CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[C:4]([F:26])[CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>CC(C)=O.O>[C:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:25])[CH2:9][N:10]([CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:11]2)=[C:4]([F:26])[CH:3]=1)([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]
Reactant: Nc1ccc(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccc(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)c(F)c1)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 3-(4-amino-2-fluorophenyl)-3-hydroxy-1-(1,1-diphenylmethyl)azetidine (Example 81, Step 1, 5.10 g, 14.7 mmol) in acetone (75 mL) was added a solution of sodium bicarbonate (2.52 g, 30.0 mmol) in water (40 mL) to give a creamy suspension. Benzyl chloroformate (2.57 g, 15.1 mmol) was added and stirring continued overnight. The suspension was filtered and the acetone evaporated. The residue was partitioned between ethyl acetate (200 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and evaporated to leave an amber foam. Chromatography over silica gel (150 g, 40-60 μM) eluting with 1-2% methanol-methylene chloride gave the title compound as a cream foam. HRMS: meas. 483.2087, theory 483.2084.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>[Ni].C(O)C>[CH2:1]([N:8]([CH2:9][CH2:10][CH2:11][NH2:12])[CH2:13][CH2:14][CH2:15][NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCN(CCC#N)Cc1ccccc1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NCCCN(CCCN)Cc1ccccc1
Reaction time: 48 h
Yield: 89.7 %

Procedure:
A mixture of 43.3 g (0.203 mol) of N-benzylbis (2-cyanoethyl)amine, 7.8 g of a 50% aqueous slurry of Raney nickel and 90 mL of a 1.4M solution of NaOH in 95% ethanol was hydrogenated in a Parr apparatus for 48 h. The catalyst was removed by filtration and washed with 80 mL of 95% ethanol. The combined filtrates were concentrated by rotary evaporation. A solution of the residue in 100 mL of hexane/chloroform (1:1, v/v) was dried over Na2SO4, filtered and concentrated by rotary evaporation. Removal of solvent residues under vacuum (0.5 mm) afforded 40.3 g (90%) of product as a yellow oil. 1H NMR (CDCl3 /TMS) δ 7.31 (m, 5 H), 3.52 (s, 2 H), 2.70 (t, J=6.8 Hz, 4 H), 2.45 (t, J=6.8 Hz, 4 H), 1.60 (quint., J=6.8 Hz, 4 H), 1.26 (s, 4 H). 13C NMR (CDCl3) δ 139.5, 128.3, 127.7, 126.3, 58.3, 50.9, 40.0, 30.6. IR (film, cm- 1) 3360 (br), 3270 (br), 3070 (w), 3050 (w), 3020 (m), 2920 (br. s), 2850 (s), 2800 (s), 1600 (s), 1485 (s), 1450 (s), 1360 (m), 1110 (br), 1070 (m), 1020 (m) 730 (m), 690 (m).
Reaction SMILES: C([O:5][C:6](=[O:48])[C@H:7]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:8][C:9](=[O:40])[CH2:10][N:11]([C:21](=[O:39])[C@H:22]([CH3:38])[NH:23][C@H:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)(C)(C)C.[BrH:49].CCOCC>C(O)(=O)C>[BrH:49].[CH2:36]([O:35][C:33]([C@@H:24]([NH:23][C@H:22]([C:21]([N:11]([CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1)[CH2:10][C:9]([NH:8][C@H:7]([C:6]([OH:48])=[O:5])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:40])=[O:39])[CH3:38])[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:34])[CH3:37]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)N[C@@H](Cc1ccccc1)C(=O)O)C1Cc2ccccc2C1

Procedure:
N-[1(S)-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(2-indanyl)glycyl-L-phenylalanine tert-butyl ester (1.8 g) is dissolved in 2 ml of acetic acid, and 3 ml of 30% hydrogen bromide in acetic acid is added. The mixture is reacted at room temperature for 10 minutes. The reaction mixture is shaken with 300 ml of ether and allowed to stand. The ether is then decanted off and to the precipitate is added ethyl acetate, whereby 1.35 g of N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(2-indanyl)glycyl-L-phenylalanine hydrobromide is obtained as colorless prisms melting at 177°-181° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:7]2[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=2[F:1])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Yield: 69 %

Procedure:
Dissolve 3,4-difluoronitrobenzene (2.0 g, 12.6 mmol) in acetonitrile (35 mL) and add piperazine-1-carboxylic acid tert-butyl ester (4.7 g, 25.2 mmol). Heat the mixture at reflux for 16 h. Cool the mixture to room temperature and concentrate in vacuo. Partition the residue between dichloromethane (75 mL) and water (75 mL), separate the organic portion and extract the aqueous portion with dichloromethane (2×25 mL). Combine the organics and dry (Na2SO4), filter, and concentrate in vacuo to give 2.83 g (72%) of the title compound. MS/ES m/z 270.2 [M-tertBu+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[C:12]([C:13]([OH:15])=[O:14])=[C:11]([C:16](=[O:30])[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=3[N+:27]([O-])=O)[N:10]=[N:9]2)=[CH:5][CH:4]=1.C(O)C.C(OCC)(=O)C.[H][H]>[C].[Pd].C(Cl)Cl>[NH2:27][C:18]1[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:17]=1[C:16]([C:11]1[N:10]=[N:9][N:8]([CH2:7][C:6]2[CH:31]=[CH:32][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:12]=1[C:13]([OH:15])=[O:14])=[O:30]
Reactant: [H][H]
Reactant: COc1ccc(Cn2nnc(C(=O)c3cc(OC)c(OC)cc3[N+](=O)[O-])c2C(=O)O)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nnc(C(=O)c3cc(OC)c(OC)cc3N)c2C(=O)O)cc1
Yield: 100 %

Procedure:
A 1 N aqueous sodium hydroxide solution (13 ml) was added to a solution of ethyl 1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate (b-1) (3.04 g, 6.46 mmol), prepared in step (b), in tetrahydrofuran (40 ml). The mixture was stirred at room temperature for 3.5 hr. The reaction solution was diluted with ether, and water was added thereto. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate, followed by washing with water and saturated brine solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxyic acid as light yellow oil (c-1′: LP) (2.55 g, 89%). The resultant 1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylic acid (c-1′:LP) (1.07 g, 2.42 mmol) was dissolved in a mixed solvent composed of ethanol (50 ml) and ethyl acetate (50 ml). 10% palladium-carbon (129 mg) was added thereto. The mixture was stirred in a hydrogen atmosphere at room temperature for 4 hr. Methylene chloride was added to the reaction solution to dissolve the precipitated crystal, followed by filtration through Celite. The filtrate was concentrated under reduced pressure to give 4-(2-amino-4,5-dimethoxybenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylic acid (c-1: LP) (1.06 g, 100%).