Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:12][C:13]3[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=3)[C:5]=2[CH:4]=[CH:3]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.CN(C)C=O>O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:17][C:16]2[CH:15]=[CH:14][C:13]([O:12][C:6]3[C:5]4[CH:4]=[CH:3][C:2](=[O:1])[NH:11][C:10]=4[N:9]=[CH:8][CH:7]=3)=[CH:19][CH:18]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)ccc23)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ccnc3[nH]c(=O)ccc23)cc1

Procedure:
N-(4-Fluorophenyl)-N′-{4-[(7-oxo-7,8-dihydro[1,8]naphthyridin-4-yl)oxy]aniline (30 mg), p-fluorophenyl isocyanate (0.016 ml) and dimethylformamide (6 ml) were stirred at 70° C. until disappearance of the starting materials. After returning the reaction solution to room temperature, water was added dropwise and the precipitated solid was filtered out to obtain 22 mg of a light brown solid.
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:31])[N:12]([CH2:14][CH2:15][NH:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=3)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCO>[C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:31])[N:12]([CH2:14][CH2:15][N:16]([CH2:17][C:18]3[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=3)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:38])[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCOC(=O)COc1cccc(CNCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)COc1cccc(CN(C)CCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
To a solution of ethyl {3-[({2-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]ethyl}amino)methyl]phenoxy}acetate (90 mg) in EtOH (3 mL) was added sodium triacetoxyborohydride (326 mg) at ambient temperature and the resulting mixture was stirred at ambient temperature for 18 hours. And then the reaction mixture was evaporated in vacuo and partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=20:1) to give ethyl (3-{[{2-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]ethyl}(methyl)amino]methyl}phenoxy)acetate (61.9 mg) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH:29]1[CH2:33][CH2:32][C@H:31]([CH2:34][OH:35])[CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:29]2[CH2:33][CH2:32][C@H:31]([CH2:34][OH:35])[CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: OC[C@H]1CCNC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC[C@H](CO)C3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with (S)-pyrrolidin-3-ylmethanol via General Procedure E to give 18.8 mg of 305 following reverse phase purification. MS (Q1) 463.2 (M)+
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C@H:12](O)[CH2:11]4)[C@@:6]1([OH:21])[CH2:5][CH2:4][CH2:3]2.[H-].[Na+].C(Br)C=C>O1CCCC1>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11]4)[C@@:6]1([OH:21])[CH2:5][CH2:4][CH2:3]2
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)CCC[C@]12O
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C[C@]12CCCC[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)CCC[C@]12O
Reaction time: 20 h

Procedure:
To a solution of 6.05 g of 17β-12-(1,3-dioxolanyl)]-5β-androstan-3β,14β-diol in 80 ml of dry tetrahydrofuran. 5.80 g of sodium hydride (60% dispersion in mineral oil) were added under nitrogen atmosphere at room temperature and the resulting mixture was stirred at reflux temperature for 6 hrs. Alter cooling. 18.0 g of allyl bromide were added and the reflux continued for further 20 hrs. The mixture was quenched with water and the organic solvent was distilled under reduced pressure. The residue was extracted with ethyl acetate; the organic solution was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by flash-chromatography using n-hexane/ethyl acetate 80/20 as the eluant to give 5.20 g of 3β-prop-(2-en)oxy-17β-(1,3-dioxolanyl)]-5β-androstan-14β-ol as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.F[C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[N:26][CH:27]=1.O>CC(N(C)C)=O>[C:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][CH:8]([O:7][C:22]2[CH:27]=[N:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=[N+]([O-])c1ccc(F)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])nc2)CC1
Reaction time: 1 h
Yield: 49.7 %

Procedure:
Add potassium tert-butoxide (4.84 g) to a solution of tert-butyl 4-hydroxy-1-piperidine-carboxylate (8.76 g) in dimethylacetamide (DMA, 39 mL) at 0° C. under nitrogen. Stir for 1 h and add drop wise a solution 5-fluoro-2-nitro-pyridine (5 g) in DMA (78 mL). Let the reaction stir at RT overnight. Add water and stand for 1 h. Filter, wash with water. Purify by silica gel column chromatography eluting with DCM/EA (0-15%) to afford 5.65 g of the title compound. MS (ES+): m/z=324 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[CH:3]=1.Br[CH2:24][C:25]1[CH:41]=[CH:40][C:28]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=1.CC(C)([O-])C.[K+]>C1COCC1>[CH3:1][C:2]1[N:6]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:29][Si:30]([CH:31]([CH3:33])[CH3:32])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[CH:40][CH:41]=2)[N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:20])([F:22])[F:21])=[CH:16][CH:17]=3)[N:8]=2)[CH:3]=1
Reactant: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Reactant: CC(C)[Si](Oc1ccc(CBr)cc1)(C(C)C)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C
Yield: 47 %

Procedure:
To a mechanically stirred solution of 5-(5-methyl-1H-pyrazol-3-yl)-3-[4-(trifluoromethoxy)-phenyl]-1,2,4-oxadiazole (Intermediate C, 600 mg, 1.93 mmol) and [4-(bromomethyl)-phenoxy][tris(1-methylethyl)]silane (Intermediate M, 1.11 g, 2.90 mmol) in dry THF (15 mL) was added potassium tert-butoxide (239 mg, 2.13 mmol) at a temperature of 0° C. The cooling bath was removed, and the reaction mixture was stirred at rt over night. After the addition of water (75 mL), the crude product was extracted into ethyl acetate (3×75 mL). The combined organic extracts were successively washed with water and brine, dried over anhydrous magnesium sulfate, followed by filtration and evaporation of the solvent. The residue was subjected to preparative HPLC to afford the title compound (519 mg, 47%) and, additionally, a considerable amount of the product of the next step (180 mg, 22%) which was formed by cleavage of the silicon-oxygen bond under the acidic HPLC conditions.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Cl:16])[C:5]([NH:8][NH:9]C(=O)C(F)(F)F)=[N:6][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CCO.O>[Br:1][C:2]1[N:3]=[C:4]([Cl:16])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1
Reactant: O=C(NNc1ncc(Br)nc1Cl)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NNc1ncc(Br)nc1Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
N′-(5-bromo-3-chloropyrazin-2-yl)-2,2,2-trifluoroacetohydrazide G-1 (1.59 g; 4.97 mmol) is dissolved in 30 ml EtOH and treated with 3 ml conc. HCl. It is stirred for 2 hours at 100° C. The reaction mixture is cooled down, diluted with water and then the pH adjusted to 8 with saturated NaHCO3 solution. The water phase is extracted with EtOAc, the organic layer dried over MgSO4 and evaporated to dryness.
Reaction SMILES: Cl.Cl.[CH2:3]([N:6]([CH2:15][CH:16]=[CH2:17])[C:7]1[N:12]=[N:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=1)[CH:4]=[CH2:5].C([O-])(=O)C.[Na+].[CH3:23][C:24](=O)[CH2:25][CH2:26][C:27](=O)[CH3:28]>C(O)(=O)C>[CH2:15]([N:6]([CH2:3][CH:4]=[CH2:5])[C:7]1[N:12]=[N:11][C:10]([NH:13][N:14]2[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]2[CH3:23])=[CH:9][CH:8]=1)[CH:16]=[CH2:17]
Reactant: C=CCN(CC=C)c1ccc(NN)nn1
Reactant: CC(=O)CCC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: C=CCN(CC=C)c1ccc(Nn2c(C)ccc2C)nn1

Procedure:
To 7 g (25 m moles) of 6-diallylamino-3-hydrazino-pyridazine dihydrochloride (Ger. Appl. 2.002.107; C.A. 73, 66596, 1970), and 4.1 g (50 m moles) of sodium acetate dissolved in 40 ml of acetic acid, 3.42 g (30 m moles) of 2,5-hexanedione are added.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][N:5]2[CH:13]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C(C)=CC=CC=1>[C:14]([C:13]1[N:5]2[CH2:6][CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:4]2=[CH:3][C:2]=1[Cl:1])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1CCn2cc(Cl)cc21
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1C
Product: COC(=O)C1CCn2c1cc(Cl)c2C(=O)c1ccccc1

Procedure:
A solution of 1.10 g. of methyl 6-chloro-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (5.5 mmol.) in dry xylene (25 ml.) containing 2.32 g of benzoyl chloride (16.5 mmol.) is heated at reflux temperature for 50 hours. The solvent is removed in vacuo, the residue is dissolved in dichloromethane (50 ml.), the solution is washed sequentially with saturated sodium chloride solution, 10% sodium bicarbonate solution, and saturated sodium chloride solution again. The organic phase is dried over sodium sulfate, evaporated in vacuo and the residue is subjected to column chromatography on silica gel (50:1) using hexane-ethyl acetate (9:1) as the eluting solvent. The solvent is removed and the product is crystallized from hexane to give methyl 5-benzoyl-6-chloro-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, m.p. 106° C.
Reaction SMILES: C([N:8](C(OCC1C=CC=CC=1)=O)[C@@H:9]1[C@@H:15]([OH:16])[C@H:14]([O:17][C@@H:18]2[O:26][C@H:25]([CH2:27][OH:28])[C@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]2[OH:20])[C@@H:13]([CH2:29][OH:30])[O:12][CH:10]1[OH:11])C1C=CC=CC=1.Cl>CO.[Pd]>[OH:11][CH:10]1[O:12][C@H:13]([CH2:29][OH:30])[C@@H:14]([O:17][C@@H:18]2[O:26][C@H:25]([CH2:27][OH:28])[C@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]2[OH:20])[C@H:15]([OH:16])[C@H:9]1[NH2:8]
Reactant: O=C(OCc1ccccc1)N(Cc1ccccc1)[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O
Reaction time: 8 h
Yield: 82.9 %

Procedure:
N-benzyl,N-benzyloxycarbonyl lactosamine (200 mg) was dissolved in MeOH (30 mL) and HCl in MeOH (400 μL, 1.4 mmol/mL) added to the mixture followed by addition of Pd/C (50 mg) and stirred under H2 (20 bar) for 8 h. The catalyst filtered off and the filtrate concentrated affording lactosamine (100 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:36]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(C)cccc1Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=S)c1c(C)cccc1Cl
Temperature: 95 °C
Reaction time: 24 h

Procedure:
To a mixture of N-[(2-chloro-6-methylphenyl)carbonyl]-4-nitro-L-phenylalanine methyl ester (9.66 mmol, 3.64 g) and Lawesson's reagent (6.0 mmol, 2.46 g, 0.62 equiv.) was added toluene (15 mL, which had been stored over 4 A molecular sieves) at room temperature. The suspension was heated to 90-100° C. and was stirred for 24 h. Examination of the resulting clear solution by TLC failed to detect the presence of starting material. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL), saturated sodium bicarbonate solution (50 mL), and brine (50 mL). The organic extract was dried (MgSO4) filtered and evaporated under reduced pressure. The crude compound was purified by careful silica gel column chromatography (hexane:ethyl acetate, 4:1 to 2:1) to obtain 1.52 g (40%) of N-[(2-chloro-6-methylphenyl)thioxomethyl]-4-nitro-L-phenylalanine methyl ester as a yellow solid, mp 150-153° C. (triturated from diethyl ether/ hexane 3:1 ratio). HRMS: Obs. mass, 393.0685. Calcd. mass, 393.0677 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@H:9]([CH:13]=[CH2:14])[O:8][C@:7](/[CH:19]=[CH:20]/[CH:21]3[CH2:23][CH2:22]3)([C:15]([F:18])([F:17])[F:16])[C:6]=2[CH:24]=1.[N+](=[CH2:27])=[N-]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@H:9]([CH:13]3[CH2:27][CH2:14]3)[O:8][C@:7](/[CH:19]=[CH:20]/[CH:21]3[CH2:23][CH2:22]3)([C:15]([F:16])([F:17])[F:18])[C:6]=2[CH:24]=1
Reactant: C=[N+]=[N-]
Reactant: C=C[C@@H]1O[C@](/C=C/C2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: O=C1Nc2ccc(Cl)cc2[C@@](/C=C/C2CC2)(C(F)(F)F)O[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 73 mg of rel-(3S,5S)-trans-7-chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one (from Example 42) in 7.5 mL of anhydrous ether was added first 4 mg of palladium (II) acetate and then a solution of approximately 1.23 mmol of diazomethane in 3.5 mL of ether. After stirring 30 min at room temperature, the reaction mixture was filtered through a pad of filter-aid and he filtrate was evaporated to dryness. The crude product was purified by column chromatography over silica gel (elution with methylene chloride) to give 47 mg of the title compound as a pure solid was recrystallized from ether-hexanes to afford 31 mg: mp 143-144°; HRMS: Calcd. for C18H16NO2F3Cl (M-H)- : 370.0822. Found: 370.0801.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.C[O:45][C:46](=[O:63])[C@@H:47]([NH2:62])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([NH:62][C@@H:47]([CH2:48][C:49]5[CH:54]=[CH:53][C:52]([C:55]6[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=6)=[CH:51][CH:50]=5)[C:46]([OH:45])=[O:63])=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C)cc2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound (19 mg) was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (30 mg) and (S)-2-amino-3-(4′-methyl-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to General Procedures L and B. LCMS (m/z): 842.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.CC(C)([O-])C.[K+].Br[C:21]1[CH:22]=[C:23]2[N:32]([CH3:33])[CH:31]=[CH:30][C:24]2=[N:25][C:26]=1[C@@H:27]([NH2:29])[CH3:28]>>[NH2:29][C@H:27]([C:26]1[N:25]=[C:24]2[CH:30]=[CH:31][N:32]([CH3:33])[C:23]2=[CH:22][C:21]=1[N:2]([CH3:1])[CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:4]1)[CH3:28]
Reactant: CNC1CN(C(=O)OC(C)(C)C)C1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C[C@H](N)c1nc2ccn(C)c2cc1N(C)C1CN(C(=O)OC(C)(C)C)C1

Procedure:
Into a 8 mL 2-necked round-bottom flask equipped for stirring and fitted with a septum cap were added tert-butyl 3-(methylamino)azetidine-1-carboxylate (0.220 g, 1.181 mmol), potassium tert-butoxide (0.132 g, 1.181 mmol) and 2-Me THF (2 mL). The reaction mixture was heated to 85° C. (S)-1-(6-Bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (0.100 g, 0.394 mmol) in 2-Me THF (2.000 mL) was added dropwise via syringe and the reaction mixture was stirred at 85° C. for 37 minutes. The reaction mixture was then cooled and partitioned between water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and dried under vacuum. The crude product was purified by preparative HPLC (acid mode, 20-45% ACN/water gradient) to give the title compound as a light brown film (27.4 mg, 15%). ESI-MS m/z [M+H]+ calc'd for C19H29N5O2, 360. found 360.
Reaction SMILES: [CH2:1]([N:8](C)[CH:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)=[CH:11][CH2:10]1)C1C=CC=CC=1>CO>[CH3:22][N:21]([CH3:23])[C:17]1[CH:16]=[C:15]([CH:12]2[CH2:13][CH2:14][CH:9]([NH:8][CH3:1])[CH2:10][CH2:11]2)[CH:20]=[CH:19][N:18]=1
Reactant: CN(C)c1cc(C2=CCC(N(C)Cc3ccccc3)CC2)ccn1
Solvent: CO
Product: CNC1CCC(c2ccnc(N(C)C)c2)CC1
Reaction time: 3 h
Yield: 71 %

Procedure:
4-(4-(Benzyl(methyl)amino)cyclohex-1-enyl)-N,N-dimethylpyridin-2-amine (340 mg, 1.06 mmol, 1.0 eq.) was dissolved in MeOH (10 ml) and degassed with argon. Pd(OH)2 (170 mg) was then added and hydrogenation was carried out for 3 hours. After monitoring by TLC, the reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure and purified by column chromatography (Alox, 2% MeOH in DCM). Yield: 71% (175 mg, 0.75 mmol)
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[N+:8]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([O-:10])=[O:9]>C(O)=O>[N+:8]([C:11]1[CH:17]=[CH:16][C:14]([NH:15][CH:5]=[O:7])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 12 ml. of formic acid and 20 ml. of acetic anhydride (which has been stirred at room temperature for 45 minutes) is added 5 g. (0.036 m.) of p-nitroaniline. After stirring for five hours at room temperature, the reaction mixture is filtered to give p-nitroformanilide, m.p. 195°-199° C. The latter, 3 g. (0.018 m.), is hydrogenated at room temperature in a mixture of 150 ml. of ethanol and 0.3 g. of 10% palladium-on-carbon in a Parr apparatus until the calculated amount of hydrogen is absorbed. The catalyst is filtered off and the solvent is removed in vacuo to leave p-aminoformanilide.
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:4][N:5]2[C:10]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][C:6]=12.[F:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1>>[CH:12]1([NH:11][C:10]2[N:5]3[N:4]=[C:3]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[C:2]([C:29]4[CH:28]=[CH:27][N:26]=[C:25]([F:24])[CH:30]=4)=[C:6]3[CH:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2Br)cc1
Reactant: OB(O)c1ccnc(F)c1
Product: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(F)c2)cc1
Yield: 72 %

Procedure:
In a similar manner to that in Example 28, from 3-bromo-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (240 mg, 0.64 mmol) and 2-fluoropyridin-4-ylboronic acid (271 mg, 1.92 mmol) after heating to 100° C. for 1.5 hours was formed N-cyclopentyl-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-α]pyridin-7-amine (180 mg, 72%) as a greenish solid. 1H NMR (CDCl3): δ 8.12 (d, 1H), 7.56 (m, 2H), 7.27 (m, 1H), 7.13–7.02 (m, 4H), 6.90 (s, 1H), 6.05–6.01 (m, 2H), 4.02 (m, 1H), 2.16 (m, 2H), 1.86–1.68 (m, 6H); 19F NMR (CDCl3) δ −68.65, −113.06; MS m/z 391 (M+1).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1>>[Br:15][C:16]1[CH:21]=[C:20]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:19]=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Brc1cncc(Br)c1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cncc(Br)c1

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), and 3,5-dibromopyridine (purchased from Avocado Research Chemicals, Ltd.) were coupled according to the procedure described in Example 1A to provide the title compound. MS (DCI/NH3) m/z 354 (M+H)+.
Reaction SMILES: C[C@H]([NH:36][C:37]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])=O)C(N[C@H](C(N1[C@H](C(N[C@H](C(SCC2C=CC=CC=2)=O)CC2C=CC=CC=2)=O)CCC1)=O)C)=O.FC(F)(F)[C:46]([O-:48])=[O:47]>>[NH2:36][C@H:37]([C:46]([OH:48])=[O:47])[CH2:39][CH2:40][C:41](=[O:42])[OH:43]
Reactant: O=C([O-])C(F)(F)F
Reactant: C[C@H](NC(=O)CCC(=O)O)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)SCc1ccccc1
Product: N[C@@H](CCC(=O)O)C(=O)O
Reaction time: 2 h

Procedure:
First, 10 g of carboxypeptidase B (Sigma) was added to 100 pl of a solution of the (Glu-OC)-Lys monomers obtained in the above step (6), and the mixture was left for 2 hr at 37° C. Then the reaction was stopped by the addition of 50.1 of 0.1% trifluoroacetate solution. The mixture was separated by high-pressure liquid chromatography with use of a C18 reversed-phase column, and Glu-OC was obtained quantitatively.