Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH:20]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:20]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Chlorophenyl boronic acid (1.08 g, 6.97 mmol) and 3-methoxycarbonylmethyl-piperazine-1-carboxylic acid tert-butyl ester (0.9 g, 3.48 mmol) were dissolved in dichloromethane. To this mixture was added copper acetate (0.63 g, 3.48 mmol), 4 Å molecular sieves and pyridine (0.56 mL, 6.97 mmol) and the reaction mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated in vacuo and dissolved in ethyl acetate, filtered through celite and concentrated. The crude product was purified using gradient elution from hexane/ethyl acetate (5%) to hexane/ethyl acetate (20%). ESI-MS m/z: 369 (M+1), UV retention time: 2.97 min.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[Cl:18][CH2:17][CH2:16][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: ClCCBr
Reactant: Oc1ccc(Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: ClCCOc1ccc(Cc2ccccc2)cc1
Yield: 86 %

Procedure:
A solution of 4-(benzyl)phenol (638 mg, 3.46 mmol), 1-bromo-2-chloroethane (2.3 mL, 27.7 mmol) and cesium carbonate (4.5 g, 27.7 mmol) in 35 mL of acetonitrile was heated at reflux for 12 hours. After cooling, water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 734 mg of 1-(2-chloroethoxy)-4-(benzyl)benzene, 1H NMR (300 MHz, CDCl3) δ 7.29 (dd, 2H), 7.19 (dd, 1H), 7.18 (d, 2H), 7.12 (d, 2H), 6.85 (d, 2H), 4.21 (t, 2H), 3.93 (s, 2H), 3.80 (t, 2H) ppm.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:4]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21](=[O:55])[N:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]3[N:32]=[CH:33][N:34](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:35]=3)=[CH:26][N:25]=2)[CH:23]=1>CC#N>[Cl:17][C:18]1[CH:19]=[CH:20][C:21](=[O:55])[N:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]3[N:32]([CH2:2][C:3]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:4]=4)[CH:33]=[N:34][CH:35]=3)=[CH:26][N:25]=2)[CH:23]=1
Reactant: N#Cc1ccc(CBr)cc1OCC(F)(F)F
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCC(F)(F)F
Temperature: 60 °C

Procedure:
4-Bromomethyl-2-(2,2,2-trifluoro-ethoxy)-benzonitrile from Step 3 (200 mg, 0.68 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (360 mg, 0.68 mmol) were dissolved in CH3CN (3.5 ml) and heated to 60° C. for 4 hours. The solvent was removed in vacuo and redissolved in MeOH (3.5 ml). The reaction mixture was heated to 60° C. for 3 more hours. The solvent was removed in vacuo and the crude residue purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2 ] to yield the final product.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].O.[CH3:15]S(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:3]([C:7]1[S:11][C:10]([CH:12]=[CH2:15])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CS(C)=O
Reactant: CC(C)(C)c1ccc(C=O)s1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Solvent: O
Product: C=Cc1ccc(C(C)(C)C)s1
Temperature: 15 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
Sodium hydride (6.05 g-50% suspension in oil, 0.126 mol) was washed with petroleum ether, suspended in dry DMSO (90 ml) and heated with stirring at 60°-70° C. for 2 hours. The reaction mixture was then cooled to 15° C. and methyltriphenylphosphonium bromide (44.5 g, 0.125 mmol) was added portionwise with rapid stirring over a 1/2 hour period. The reaction mixture was stirred at room temperature for a further 1 hour after the addition and 5-t-butyl-2-thiophenecarboxaldehyde (21.01 g, 0.125 mol) was added dropwise over a period of 1 hour. The resultant reaction mixture was stirred at room temperature for 12 hours, poured into water (300 ml) and extracted with ether (4×150 ml). The ethereal extracts were washed with water (4×100 ml) and dried over anhydrous sodium sulphate. Removal of the solvent gave a yellow oil which was purified by column chromatography (silica eluted with hexane) to give (5-t-butylthiophen-2-yl)-ethylene (5.25 g, 25%). Ethyl diazoacetate (4.69 g, 0.041 mol) in dry dichloromethane (80 ml) was added dropwise to a solution of (5-t-butylthiophen-2-yl)-ethylene (5.1 g, 0.031 mol) and anhydrous copper (II) sulphate (0.3 g) in dry dichloromethane (20 ml) at 90° C. by means of a syringe pump over a period of 5 hours. The dichloromethane was distilled over during the addition. After complete addition the remaining dichloromethane was removed in vacuo and the resulting brown oil purified by column chromatography (silica eluted with petroleum ether/ethyl acetate 19:1) to give ethyl 2-(5-t-butylthiophen-2-yl)-cyclopropanecarboxylate (4.72 g, 60%).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[Br:20][C:21]1[C:30]([NH2:31])=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][O:24][C:25]2=[O:26].O>CC(N(C)C)=O>[Br:20][C:21]1[C:30]([NH:31][C:5](=[O:7])[C:4](=[O:8])[CH2:3][C:2]([CH3:1])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][O:24][C:25]2=[O:26]
Reactant: Nc1ccc2c(c1Br)COC2=O
Reactant: CC(C)(CC(=O)C(=O)O)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Reaction time: 0.33 h
Yield: 86.5 %

Procedure:
412 mg of 4-methyl-4-phenyl-2-oxovaleric acid is dissolved in 10 ml of dimethylacetamide and mixed under argon at −8° C. with 261 mg of thionyl chloride. After 20 minutes of stirring at −3 to +3° C., 228 mg of 4-bromo-5-aminophthalide is added. It is stirred for 1.5 hours at room temperature, then mixed with water, extracted with ethyl acetate, the organic phase is washed with water, dried (Na2SO4) and after the solvent is concentrated by evaporation and after treatment with diethyl ether, 360 mg of 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide, melting point 150-152° C., is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=1.[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].[H-].[Na+].Cl>C(OC(=O)C)C>[CH:8]1([C:7]2[C:2]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[CH:3][C:4]([C:11]([OH:13])=[O:12])=[N:5][CH:6]=2)[CH2:10][CH2:9]1
Reactant: O=C(O)c1cc(Cl)c(C2CC2)cn1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
To a solution of 4-Chloro-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48b, 680 mg, 3.44 mmol) were added 2,2,2-trifluoroethanol (CAN 75-89-8, 1.03 g, 746 μl, 10.3 mmol) and sodium hydride 60% (551 mg, 13.8 mmol) by portions. The reaction mixture was stirred at room temperature for 30 min and then stirred at 120° C. for 18 h. The reaction mixture was cooled down, diluted with ethylacetate and poured in a separatory funnel. The mixture was extracted with an aqueous 4.0M solution hydrochloric acid (6.88 ml, 27.5 mmol). The organic phase was collected. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (420 mg, 47%) as light brown solid. MS (ESI, m/z): 260.2 (M−H+)
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:23]([O:25]CC1C=CC=CC=1)=[O:24])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:13]([O:15]CC1C=CC=CC=1)=[O:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:6].C(O)C.[H][H]>[Pd].O>[NH2:1][C@H:2]([C:23]([OH:25])=[O:24])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: [H][H]
Reactant: CCCC[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCCC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 7.1 %

Procedure:
Z-Glu(Nle-OBzl)-OBzl (4.05 g) and 5% palladium on carbon (5% palladium/carbon, 0.40 g) were added to a mixed solution of ethanol (50 mL) and water (10 mL), and a catalytic reducing reaction was carried out at 50° C. overnight (14 hours) in a hydrogen gas atmosphere. Water (10 mL) was added to the reaction system in small portions during the reaction. The palladium/carbon was removed from the reaction system through filtration and the resulting filtrate was concentrated under reduced pressure. The residue was recrystallized from a small amount of water and ethanol to thus give γ-Glu-Nle (0.29 g) as hygroscopic crystals. Furthermore, the crystals were dissolved in water (30 mL) followed by the lyophilization of the solution to give γ-Glu-Nle (0.13 g, 0.50 mM) as a white powder. The characteristic values thereof will be given below:
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@:16]([F:18])([CH3:17])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@:16]([F:18])([CH3:17])[CH2:15][N:14]([C:28]([C:25]4([C:23]#[N:24])[CH2:27][CH2:26]4)=[O:29])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: C[C@]1(F)CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: N#CC1(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@]1(F)CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A mixture of 6-bromo-4-(((3R,4S)-4-fluoro-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (100 mg, 0.207 mmol), 1-cyanocyclopropanecarboxylic acid (27.5 mg, 0.248 mmol), Hunig's base (0.144 mL, 0.826 mmol) and BOP (110 mg, 0.248 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 h. The resulting mixture was diluted with ethyl acetate (80 mL) and washed with saturated NaHCO3, water, brine, dried (MgSO4) and concentrated to give crude 6-bromo-4-(((3R,4S)-1-(1-cyanocyclopropanecarbonyl)-4-fluoro-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (70 mg), which was taken to the next step without purification. MS (ES+) m/z: 449.0 (M+H).
Reaction SMILES: [Na].[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC[CH2:11][C:12]1[CH:23]=[CH:22][C:15]([O:16][CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1.C1C(CO)=CC=C(O)C=1.BrC(C)C(OCC)=O.OCC1C=CC(OC(C)C(O)=O)=CC=1>C(O)C>[O:8]([CH2:11][C:12]1[CH:23]=[CH:22][C:15]([O:16][CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(CCBr)cc1)C(=O)O
Reactant: Oc1ccccc1
Agent: CC(Oc1ccc(CO)cc1)C(=O)O
Agent: CCOC(=O)C(C)Br
Agent: OCc1ccc(O)cc1
Solvent: CCO
Product: CC(Oc1ccc(COc2ccccc2)cc1)C(=O)O

Procedure:
2.3 g. of sodium is dissolved in 250 ml. of absolute ethanol; 9.4 g. of phenol and 28.6 g. of the ethyl ester of 2-(p-bromoethylphenoxy)-propionic acid [obtainable by reacting p-hydroxybenzyl alcohol with ethyl 2-bromopropionate to the ethyl ester of 2-(p-hydroxymethylphenoxy)-propionic acid and subsequent reaction with SOBr2 ] are added thereto, and the mixture is refluxed for 3 hours and evaporated. The usual working-up procedure yields the ethyl ester of 2-(4-phenoxymethylphenoxy)-propionic acid. Analogously, the ethyl ester of 2-(4-phenoxymethylphenoxy)-2-methylpropionic acid is obtained from the ethyl ester of 2-p-bromomethylphenoxyisobutyric acid (obtainable by bromination of the ethyl ester of 2-p-methylphenoxyisobutyric acid with N-bromosuccinimide);
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([C:7]1[S:8][C:9]([Cl:13])=[C:10]([Cl:12])[CH:11]=1)=[O:6])C.Cl.C(Cl)Cl>CC(C)=O.O>[Cl:12][C:10]1[CH:11]=[C:7]([C:5](=[O:6])[C:4]([OH:14])=[O:3])[S:8][C:9]=1[Cl:13]
Reactant: CCOC(=O)C(=O)c1cc(Cl)c(Cl)s1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C(=O)c1cc(Cl)c(Cl)s1
Temperature: 25 °C

Procedure:
A solution of (4,5-dichlorothiophen-2-yl)-oxo-acetic acid ethyl ester (2.53 g, 10.0 mmol) in acetone (15 ml), water (5 ml), and conc. HCl (20 ml) was stirred under reflux for 2 hr. The reaction mixture was then allowed to cool to ambient temperature and was poured into CH2Cl2 and water. The organic layer was dried over Na2SO4 and concentrated under vacuum. Crystallization of the residue from dichloromethane provided pure (4,5-dichlorothiophen-2-yl)-oxo-acetic acid as a yellow solid (557 mg, 25%). MS (M−H)−: 222.78; 1H NMR (300 MHz, DMSO-d6) δ8.06 (s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH2:21][O:22][CH2:23][CH2:24][CH2:25][Mg]Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ClCCCOCC1C=CC=CC=1.[Cl-].[NH4+]>O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]([OH:11])[CH2:25][CH2:24][CH2:23][O:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cl[Mg]CCCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: ClCCCOCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)CCCOCc1ccccc1
Reaction time: 0.25 h

Procedure:
A THF solution (20 ml) of N-(tert-butoxycarbonyl)-L-prolinal (4.50 g) was dropwise added to a THF solution (30 ml) of 3-(phenylmethyloxy)propyl magnesium chloride prepared from 1-chloro- 3-(phenylmethyloxy)propane (5.00 g), at -78° C. After stirring for 15 minutes, saturated ammonium chloride (10 ml) was added, and the reaction mixture was allowed to reach room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 10% citric acid, saturated sodium hydrogencarbonate and saturated brine in order, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent: n-hexane-ethyl acetate) to give two stereoisomers (1.89 g of low polar isomer and 3.05 g of high polar isomer).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(C1CCCCC1=O)(=O)C.[CH2:28]1[NH:33][CH2:32][CH2:31][N:30]2[CH2:34][CH2:35][CH2:36][CH:29]12>CN(C=O)C.[Cu]I>[CH2:28]1[CH:29]2[CH2:36][CH2:35][CH2:34][N:30]2[CH2:31][CH2:32][N:33]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C1CC2CNCCN2C1
Agent: [Cu]I
Agent: CC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCN3CCCC3C2)cc1
Temperature: 90 °C
Reaction time: 20 h
Yield: 60.3 %

Procedure:
Methyl 4-iodobenzoate (2.076 g, 7.92 mmol), cesium carbonate (5.16 g, 15.85 mmol), 2-acetylcyclohexanone (0.209 mL, 1.58 mmol) and copper(I) iodide (0.075 g, 0.40 mmol) were added to a stirred solution of 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine (1 g, 7.92 mmol) in DMF (20 mL) under nitrogen. The resulting suspension was stirred at 90° C. for 20 h. The reaction mixture was evaporated to dryness and redissolved in a mixture of methanol and water. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 3.5M NH3/MeOH and pure fractions were evaporated to dryness to afford methyl 4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)benzoate (1.243 g, 60.2%) as a brown gum.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B].[C:22]([O-])(=[O:24])C.[Na+]>CN(C)C=O>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:22]=[O:24])=[C:16]([CH3:20])[CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccc(OCc2ccccc2)c1
Reactant: CC(=O)[O-]
Agent: [B]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)ccc1C=O
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
Dry N,N-dimethylformamide (34.2 ml, 444 mmol) was added dropwise with stirring and cooling under an argon atmosphere to phosphorous oxychloride (18.3 ml, 200 mmol) at such a rate that the temperature did not exceed 10° C. After 30 min stirring at 0° C., a solution of 1-benzyloxy-3-methyl-benzene (22 g, 111 mmol) in N,N-dimethylformamide (22 ml) was added dropwise within 30 min (for the preparation of 1-benzyloxy-3-methyl-benzene see: D. Bogdal, J. Pielichowski, A. Boron, Syn. Commun. 1998, 28, 3029-3039). The reaction mixture was stirred 30 min at ambient temperature and then continuously heated to 110° C. After 10 min at 110° C., the mixture was kept at 90° C. for 3.5 h, cooled to 10° C., neutralized with 25% aqueous sodium acetate, with cooling, and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, hexane/AcOEt=19/1) to give 4.3 g (19 mmol, 17%) of the title compound as yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([C:24]([C:26]2[CH:36]=[C:35]([CH3:37])[C:29]3[N:30]([CH3:34])[C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:21]=[CH:20][N:19]=1>CN1C(=O)CCC1.CO>[CH3:34][N:30]1[C:29]2[C:35]([CH3:37])=[CH:36][C:26]([C:24]([C:22]3[CH:21]=[CH:20][N:19]=[C:18]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:23]=3)=[O:25])=[CH:27][C:28]=2[O:32][C:31]1=[O:33]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(C(=O)c2ccnc(Cl)c2)cc2oc(=O)n(C)c12
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1cc(C(=O)c2ccnc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)c2)cc2oc(=O)n(C)c12

Procedure:
0.40 g (1.8 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 0.18 g (0.60 mmol) 6-(2-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one were stirred overnight in 3 mL NMP at 120° C. The reaction mixture was diluted with MeOH and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH:16]([C:17]([O:19]CC)=[O:18])[CH2:15][C:14]2([CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:13]1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O.CO>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH:16]([C:17]([OH:19])=[O:18])[CH2:15][C:14]2([CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:13]1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: CCOC(=O)C1CC2(CCOCC2)CN1C(=O)[C@@H](NC(=O)OC)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N1CC2(CCOCC2)CC1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a solution of ethyl 2-{N-[(methyloxy)carbonyl]-L-valyl}-8-oxa-2-azaspiro[4.5]decane-3-carboxylate (102) (310 mg, 0.84 mmol) in a 2:1:1 mixture of THF/water/methanol (6 mL) was added lithium hydroxide monohydrate (70 mg, 1.67 mmol) and the reaction stirred at room temperature for 2 h. Treated with 1 N HCl (1.6 mL), partitioned between EtOAc and water (30 mL each), organic layer extracted with EtOAc (30 mL), dried (MgSO4) and concentrated to give a white foam (211 mg, 74% yield). This material was used in subsequent steps without additional purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (br. s., 1H) 7.19-7.41 (m, 1H) 4.05-4.28 (m, 1H) 3.91-4.05 (m, 2H) 3.40-3.71 (m, 6H) 3.20-3.28 (m, 1H) 1.81-1.98 (m, 2H) 1.70-1.80 (m, 1H) 1.46-1.69 (m, 2H) 1.32-1.46 (m, 1H) 0.65-1.03 (m, 10H).
Reaction SMILES: [NH2:1][C:2](=[N:19][OH:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:5]([F:18])[CH:4]=1.[CH3:21][C:22]1[CH:27]=[C:26]([C:28](O)=O)[CH:25]=[CH:24][C:23]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37]>>[CH3:21][C:22]1[CH:27]=[C:26]([C:28]2[O:20][N:19]=[C:2]([C:3]3[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[C:5]([F:18])[CH:4]=3)[N:1]=2)[CH:25]=[CH:24][C:23]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37]
Reactant: CC(C)(C)OC(=O)CNc1ccc(C(N)=NO)cc1F
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(NCC(=O)OC(C)(C)C)c(F)c3)no2)cc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 50 (141.65 mg; 0.50 mmol) and Intermediate 3 (135.76 mg; 0.60 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as a colorless oil. LC/MS (Method B): 474.4 (M+H)+. HPLC (Method A) Rt 6.70 min (Purity: 84.4%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+]>O.CO.[Fe]>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[N:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:22]#[N:23])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: N#Cc1cnc2ncc([N+](=O)[O-])cc2c1Nc1cccc(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: N#Cc1cnc2ncc(N)cc2c1Nc1cccc(Br)c1
Yield: 78 %

Procedure:
A mixture of 11.2 g (30.3 mmol) of 4-(3-bromo-phenylamino)-6-nitro-[1.8]naphthyridine-3-carbonitrile, 5.1 g (90.8 mmol) of powdered iron, and 8.1 g (151 mmol) of ammonium chloride was mechanically stirred at reflux in a mixture of 330 ml water and 560 ml methanol for 40 min. The liquid layer was decanted from the solids and diluted with ethyl acetate, saturated sodium bicarbonate, and brine. This mixture was extract multiple times with ethyl acetate (final volume 3500 ml). The combined extracts were dried with magnesium sulfate and filter through a short column of silica gel. The solvent was removed and the residue was stirred with ether. The solid was collected and dried give 8.04 g of the title compound as an orange solid: mass spectrum (electrospray, m/e): M+H 340, 342.1.