Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19]CC4C=CC=CC=4)=[O:18])[CH2:12]3)=[C:8]([C:27](=[O:29])[NH2:28])[CH:7]=[N:6][N:5]2[CH:30]=1.BrC1C=C2[C:39](Cl)=[C:38]([C:41](N)=O)[CH:37]=NN2C=1.N[C@H]1[C@@H](C)CN(C(OCC2C=CC=CC=2)=O)C1.I[Si](C)(C)C.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.C(N(CC)C(C)C)(C)C>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][C:38]([CH3:41])([CH3:39])[CH3:37])=[O:18])[CH2:12]3)=[C:8]([C:27](=[O:29])[NH2:28])[CH:7]=[N:6][N:5]2[CH:30]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A suspension of 5.8 g (12.28 mmol) of (3S,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylate (prepared by coupling Intermediate 2 and enantiopure intermediate 5 as described in Step 1 of Example 52) in acetonitrile (75 mL) was cooled to 0° C. in an ice-water bath. Iodotrimethylsilane (6.99 mL, 49.1 mmol) was then added dropwise and the reaction mixture was stirred while the ice bath was allowed to slowly warm to room temperature. After 90 minutes, the deprotection step is complete. The reaction mixture was recooled to 0° C. and was quenched by slowly adding 35 mL MeOH. After stirring 45 minutes to ensure that the quench was complete, the volatiles were removed in vacuo to afford a solid. After drying for 1 hour under high vacuum, di-t-butyldicarbonate (4.02 g, 18.42 mmol) was weighed into the flask containing the solid. DCM (100 mL) and N,N-Di-iso-propylethylamine (10.69 mL, 61.4 mmol) were then added and the solution was stirred at room temperature. Within 15 minutes the reaction is complete and the product began to precipitate out of solution. The reaction mixture was diluted with 150 mL DCM and the resulting suspension was filtered. The filter cake was washed with 1:1 hexanes:ethyl ether and dried to afford 3.44 gm of title compound as a white solid. The DCM mother liquor was washed 2× with water and 1× brine. After drying over sodium sulfate and concentration, the residue was loaded onto a 120 gm ISCO column for purification by flash chromatography, eluting with 0-10% MeOH in DCM. Concentration of the pure fractions afforded an additional 1.13 gm of the titile compound as a light yellow solid. Concentration gave (3S,4S)-tert-butyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylate (4.57 gm; 9.90 mmol; 81% yield). MS (ES+) m/z: 438.0, 440.0 (M+H); LC retention time: 3.103 min (analytical HPLC Method O).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:16])=[C:4]([C:9]([CH3:15])=[C:10]([N+:12]([O-])=O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[NH4+].O>CO.[Fe]>[NH2:12][C:10]1[C:9]([CH3:15])=[C:4]([C:3]([F:16])=[C:2]([Br:1])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(C)c([N+](=O)[O-])cc(Br)c1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(C)c(N)cc(Br)c1F
Temperature: 70 °C
Yield: 102.3 %

Procedure:
To a solution of methyl 3-bromo-2-fluoro-6-methyl-5-nitrobenzoate (2.43 g, 8.32 mmol) in Methanol (80 ml) at room temperature was added ammonium chloride (4.37 g, 83.2 mmol) followed by deionized Water (40 ml). The mixture was heated to 70° C. in air before the addition of iron (2.79 g, 49.92 mmol). The reaction turned brown over the 2.5 hours it was stirred at 70° C. This mixture was allowed to cool to room temperature and was filtered through Kieselgel. The filter pad was washed with MeOH (80 ml) and the filtrate concentrated under reduced pressure. The residue was dissolved in saturated NaHCO3(aq) (50 ml) and EtOAc (150 ml). The phases were separated and the organic phase was washed with saturated NaHCO3(aq) (50 ml) before being dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 7:3 Heptane:EtOAc) to give 2.23 g (95%, 77% corrected yields) of methyl 3-amino-5-bromo-6-fluoro-2-methylbenzoate as a yellow oil. The material was taken through the next step without further purification. LC-MS 81%, 1.87 min (3 minute LC-MS method), m/z=261.9/263.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 6.89 (d, J=6.0 Hz, 1H), 3.94 (s, 3H), 3.60 (s, 2H), 2.08 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][S:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].C[O-].[Na+].[C:22]1(=[O:28])[CH2:27][CH2:26][CH2:25][CH:24]=[CH:23]1>CO.[NH4+].[Cl-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([S:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)(=[O:6])=[O:7])[CH:24]1[CH2:25][CH2:26][CH2:27][C:22](=[O:28])[CH2:23]1
Reactant: COC(=O)CS(=O)(=O)c1cccc2ccccc12
Reactant: O=C1C=CCCC1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)C(C1CCCC(=O)C1)S(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.4 %

Procedure:
To a stirred solution of 2.75 g (0.010 mol) of (naphthalene-1-sulfonyl)-acetic acid methyl ester in 100 mL of MeOH at RT, 0.19 mL (0.011 mol, 1.1 eq) of a solution of sodium methoxide (5.4 M in MeOH) were added. After 15 min, 1.1 g (0.011 mol, 1.1 eq) of 2-cyclohexen-1-one were added. The reaction mixture was stirred at RT for 3 hours followed by an additional 4 hours at 60° C., diluted with aqueous NH4Cl and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel with heptane/EtOAc (from 4:1 to 1:2) yielded 1.78 g (48%) of (naphthalene-1-sulfonyl)-(3-oxo-cyclohexyl)-acetic acid methyl ester as a racemic mixture of diastereomers, light orange oil, MS: 361 (MH+).
Reaction SMILES: [Cl:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].CC(C)([O-])C.[K+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[Cl:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:3]1=[O:13]
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2ccccc2CCC1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1C(=O)C(Cl)CCc2ccccc21
Reaction time: 0.25 h

Procedure:
A solution of 3-chloro-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one (1.95 g) in dimethylformamide (10 ml) was added dropwise with stirring to a solution of potassium t-butoxide (1.12 g) in dimethylformamide (10 ml) at 5°. The solution was stirred for an additional 15 minutes at 5°, then ethyl bromoacetate (1.78 g) in dimethylformamide (5 ml) was added dropwise. Stirring was continued for an additional 30 minutes at 5° and then for 3 hours at room temperature. The reaction mixture was cooled to 10° and water (100 ml) was added. The solution was extracted with chloroform (100 ml) and the chloroform solution washed with water (2×10 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 3-chloro-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one; NMR(DMSO-d6): δ1.2(t,3H); 2.65(m,4H); 4.15(q,2H); 2.6 (d,2H); 7.3(m).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:14][CH2:13][C:12]2=[O:20])=[C:7]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:6]=1)=[O:4]>[OH-].[Na+]>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:14][CH2:13][C:12]2=[O:20])=[C:7]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:6]=1)([OH:4])=[O:2]
Reactant: CCC(CC)Nc1cc(C(=O)OC)ccc1N1C(=O)CCC1(CO)CO
Agent: [Na+]
Agent: [OH-]
Product: CCC(CC)Nc1cc(C(=O)O)ccc1N1C(=O)CCC1(CO)CO
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.1 %

Procedure:
A suspension of the above ester (0.07 g, 0.19 mmol) in 1 N sodium hydroxide (1 mL) was stirred at ambient temperature for 12 h. Upon acidification of the reaction mixture with glacial acetic acid, a solid precipitated. This solid was collected by filtration and dried to give 0.05 g (75%) of the title compound as a white solid, mp 220-221° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:11][CH:10]([O:12][C:13]2[C:18]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:17][N:16]=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C>Cl.CO>[O:22]1[CH2:21][CH2:20][CH:19]([C:18]2[C:13]([O:12][CH:10]3[CH2:11][CH:8]([NH2:7])[CH2:9]3)=[N:14][CH:15]=[N:16][CH:17]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC1CC(Oc2ncncc2C2CCOCC2)C1
Agent: Cl
Solvent: CO
Product: NC1CC(Oc2ncncc2C2CCOCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
The mixture of {3-[5-(tetrahydro-pyran-4-yl)-pyrimidin-4-yloxy]-cyclobutyl}-carbamic acid tert-butyl ester (1.2 g, 3.21 mmol) in HCl/MeOH (20 mL) was stirred at room temperature for 1 hour. Then it was concentrated to give 3-[5-(tetrahydro-pyran-4-yl)-pyrimidin-4-yloxy]-cyclobutylamine (916 mg, 3.21 mmol, yield: 93%) which was used in the next step without further purification. ESI-MS (M+1): 250 calc. for C13H19N3O2 249.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][CH2:24][O:25][CH3:26])[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:27](OCC)C.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:27][O:21][C:20](=[O:22])[C@@H:19]([NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])[CH2:23][CH2:24][O:25][CH3:26]
Reactant: COCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCOCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC
Temperature: 25 °C
Yield: 94 %

Procedure:
In a flask was placed (S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-methoxy-butyric acid (500 mg, 1.41 mmol), diethyl ether (20 mL) and methanol (5 mL) and cooled to 0° C. in an ice bath. To this mixture was added a 2M solution of (trimethylsilyl)diazomethane in diethyl ether (1.41 mL, 2.82 mmol) dropwise. The mixture was stirred and warmed to 25° C. The mixture was then concentrated to afford (S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-methoxy-butyric acid methyl ester (489 mg, 94%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O.O>CN(C=O)C>[F:26][C:25]([F:28])([F:27])[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
To a solution of methyl 5-hydroxypyridine-2-carboxylate (10.1 g, 65.95 mmol) and cesium carbonate (42.9 g, 131.9 mmol) in DMF (1 L) is added a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (22.96 g, 98.93 mmol) in 20 ml of DMF over 2 hours. The reaction is stirred 4 hours at room temperature and then poured over water (1 L) and stirred for additional 1 hour. A brown solid is collected by filtration and washed with additional water. The solid is dried to a constant weight to give the intermediate compound (10.3 g 66%) of methyl 5-(2,2,2-trifluoroethoxyl)pyridine-2-carboxylate which is used without further purification. To a solution of methyl 5-(2,2,2-trifluoroethoxyl)pyridine-2-carboxylate (4.5 g, 19.1 mmol) in methanol (45 mL) is added sodium hydroxide 1 M solution (38.2 ml, 38.2 mmol) and the reaction is stirred for 2 hours at room temperature. The pH of the reaction mixture is adjusted with HCl 35% w/w to adjust pH=1 and then the resulting solid is isolated by filtration. The solid is washed with water and then dried under vacuum to give the title compound (3 g, 70%). ES/MS (m/z): 222.1 (M+1).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[F:5][C:6]([F:23])([F:22])[C:7]1[O:8][C:9]([CH2:20]Br)=[CH:10][C:11]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.P([O-])(O)(O)=O.[Na+]>O1CCCC1.[Cu](Cl)Cl>[F:23][C:6]([F:5])([F:22])[C:7]1[O:8][C:9]([CH2:20][C:1]#[CH:2])=[CH:10][C:11]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1
Reactant: C#C[Mg]Br
Reactant: FC(F)(F)c1oc(CBr)cc1COC1CCCCO1
Agent: Cl[Cu]Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCc1cc(COC2CCCCO2)c(C(F)(F)F)o1
Temperature: 20 °C

Procedure:
90 ml of ethynyl magnesium bromide as a 1M solution in tetrahydrofuran and 1.8 g of copper chloride were added to 6.18 g of the product of Stage E in 15 ml of tetrahydrofuran and the mixture was refluxed for 18 hours, cooled to 20° C., poured into a saturated aqueous sodium dihydrogenphosphate solution, and extracted with isopropyl ether. The extract was dried and the solvent evaporated. The residue was chromatographed on silica (eluent: 9/1 hexane/isopropyl ether) to obtain 1.5 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:20]12[CH2:26][CH:23]([CH:24]=[CH:25]1)[CH2:22][CH:21]2[C:27](Cl)=[O:28]>>[CH:20]12[CH2:26][CH:23]([CH:24]=[CH:25]1)[CH2:22][CH:21]2[C:27]([N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1)=[O:28]
Reactant: Clc1ccc(C23CNCC2C3)cc1
Reactant: O=C(Cl)C1CC2C=CC1C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(C1CC2C=CC1C2)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
Following the procedure of Example 8, 19.53 g. of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane, 10.59 g. of sodium carbonate and 5-norbornene-2-carbonyl chloride are reacted to give the product as a light brown-yellow oily gum.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15])=O.C1(P(=[CH:36][C:37]([O:39][CH3:40])=[O:38])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:40][O:39][C:37](=[O:38])/[CH:36]=[CH:1]/[C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15]
Reactant: CCOC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(/C=C/C(=O)OC)c([N+](=O)[O-])c1
Yield: 90.7 %

Procedure:
In 70 ml of toluene was dissolved 3.2 g of ethyl 4-formyl-3-nitrobenzoate and then 5.75 g of methyl triphenylphosphoranylideneacetate, followed by 6 hours of stirring under reflux. After cooling, the reaction solution was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 3.63 g of ethyl 4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-3-nitrobenzoate as a white solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:19]=[CH:18][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of methyl 4-(benzimidazol-2-yl)-benzoate (0.23 g, 0.9 mmol) in THF (10 mL) at 0° C. was added a solution of DIBAL-H (5.0 mL, 1.0 M in THF, 5.0 mmol). The reaction was allowed to warm to room temperature, stirred for 1 h and quenched with a saturated potassium sodium tartrate solution (20 mL). The biphasic mixture was stirred vigorously for 1 h, the phases separated and the organic layer dried (MgSO4), filtered, concentrated and purified by column chromatography on silica gel (7% MeOH/CH2Cl2) to give 4-(benzimidazol-2-yl)-benzyl alcohol (0.175 g, 87%). 1H NMR (CD4OD) δ 3.30 (s, 1H (OH)), 4.69 (s, 2H), 7.26 (m, 2H), 7.53 (d, 2H, J=8.4 Hz), 7.60 (m, 2H), 8.07 (d, 2H, J=8.1 Hz).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[F-].[K+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1B1OC(C)(C)C(C)(C)O1>O1CCCC1>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[F:13])[C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1c(F)cccc1Br
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1c(F)cccc1-c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
A suspension of 2-bromo-6-fluorobenzonitrile (2.50 g, 12.5 mmol), potassium fluoride (2.40 g, 41.3 mmol) and 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4.67 g, 17.5 mmol) in tetrahydrofuran (50 ml) was degassed with nitrogen for 30 min. Tris(dibenzylideneacetone)dipalladium(0) and tri-tert-butylphosphine (0.2M solution in 1,4-dioxane, 3.7 ml) were added and the mixture stirred at ambient temperature for 15 min then at 50° C. for 18 h. After cooling to ambient temperature, the resulting dark suspension was poured onto 0.5M sodium hydroxide solution (500 ml) and stirred vigorously for 2 h. The dark solid was collected by filtration, washed with water (100 ml) and isohexane (50 ml) and left to air dry which gave 3,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a brown/black solid (3.25 g, 100%): δH (360 MHz, CDCl3) 7.32-7.44 (3H, m), 7.71-7.77 (1H, m), 8.35-8.41 (2H, m). 3,2′-Difluoro-5′-nitrobiphenyl-2-carbonitrile (3.25 g, 12.5 mmol) in tetrahydrofuran (20 ml) and ethanol (20 ml) was treated with tin(II) chloride dihydrate (9.86 g, 43.8 mmol) and the mixture left to stir at ambient temperature for 18 h. The solvent was evaporated and the residue stirred with 2N sodium hydroxide solution (40 ml) for 2 h. The resulting suspension was diluted with water (100 ml) and extracted with dichloromethane (3×200 ml). The combined organics were washed with water (200 ml), brine (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give 5′-amino-3,2′-difluorobiphenyl-2-carbonitrile as a brown solid (2.87 g, 100%): δH (360 MHz, CDCl3) 3.74 (2H, s), 6.66-6.75 (2H, m), 7.01 (1H, dd, J 9 and 9), 7.19-7.30 (2H, m), 7.59-7.65 (1H, m).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](Cl)=[C:17]([C:20]([NH2:22])=[O:21])[CH:16]=[N:15][N:14]2[CH:23]=1.[NH2:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH3:34])([C:30]([O:32][CH3:33])=[O:31])[C:26]1([CH3:36])[CH3:35]>CN1C(=O)CCC1.C(OCC)(=O)C>[Br:10][C:11]1[CH:12]=[C:13]2[C:18]([NH:24][C@@H:25]3[CH2:29][CH2:28][C@:27]([CH3:34])([C:30]([O:32][CH3:33])=[O:31])[C:26]3([CH3:36])[CH3:35])=[C:17]([C:20](=[O:21])[NH2:22])[CH:16]=[N:15][N:14]2[CH:23]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: COC(=O)[C@@]1(C)CC[C@@H](N)C1(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C1(C)C
Temperature: 90 °C
Yield: 57.4 %

Procedure:
Hunig's base (1.27 mL, 7.29 mmol) was added to a solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 625 mg, 2.277 mmol) and (1S,3R)-methyl 3-amino-1,2,2-trimethylcyclopentanecarboxylate (464 mg, 2.505 mmol) in NMP (5692 n1). The reaction was heated at 90° C. for 14 hrs. The reaction was cooled to room temperature and diluted with ethyl acetate (20 ml). The ethyl acetate solution was washed with water (3×10 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure to give a light yellow oil. The crude product was chromatographed on the silica gel column eluted with 0-50% ethyl acetate in hexane to afford the title compound (583 mg, 1.308 mmol, 57.5% yield) as a white solid. LC/MS found [M+H]+=425.1. 1H NMR (400 MHz, MeOD) δ ppm 8.13 (1 H, s), 7.60-7.66 (1 H, m), 6.88-6.95 (1 H, m), 4.43-4.52 (1 H, m), 3.71 (3 H, s), 2.62-2.71 (1 H, m), 2.31-2.39 (1 H, m), 1.65-1.76 (1 H, m), 1.55-1.64 (1 H, m), 1.32 (3 H, s), 1.09 (3 H, s), 0.98 (3 H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[C:15](=[O:18])[CH2:16][CH3:17].Cl.[N:20](OCCCC)=[O:21]>C(OCC)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[C:15](=[O:18])[C:16](=[N:20][OH:21])[CH3:17]
Reactant: CCCCON=O
Reactant: CCC(=O)c1cc(OC)c2ccccc2c1OC
Agent: Cl
Solvent: CCOCC
Product: COc1cc(C(=O)C(C)=NO)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
The product from Step A (1.28 g, 5.24 mmol) was dissolved in ethyl ether (50 mL), anhydrous hydrogen chloride gas was added through this solution at moderate rate for 5 min. Butyl nitrite (0.68 mL, 5.77 mmol) was then added dropwise. Hydrogen chloride bubbling was continued for an additional 10 min. after addition of butyl nitrite was completed, the reaction mixture was then stirred at room temperature for 4 hr. The volatiles were removed by evaporation under vacuum and the residue was purified by flash chromatography (silica gel, ethyl acetate/hexane: 0.5/9.5) to give an oil (0.8 g): MS 274 (M+1).
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14]C(C)(C)C)=O)=[N:4][CH:3]=1.Cl.[CH3:20][O:21][C@H:22]([CH3:32])[C@H:23]([NH:27][C:28]([O:30][CH3:31])=[O:29])C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Li+].[OH-]>C(Cl)Cl.CO.CN(C=O)C>[Br:1][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12](=[O:14])[C@@H:23]([NH:27][C:28](=[O:29])[O:30][CH3:31])[C@H:22]([O:21][CH3:20])[CH3:32])=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(Br)[nH]1)[C@@H](C)OC
Temperature: 40 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of (5)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.00 g, 3.2 mmol) in a mixture of CH2Cl2 (30 mL) and MeOH (5 mL) was added HCl (in dioxane, 4 M, 11.5 mL, 46.0 mmol). The solution was stirred at 40° C. for 1 h, cooled to room temperature, and concentrated to dryness under reduced pressure. To the crude intermediate suspended in CH2Cl2 (30 mL) was added (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (0.67 g, 3.5 mmol), HATU (1.47 g, 3.8 mmol), and DIPEA (1.00 mL, 6.0 mmol). The resulting solution was stirred at room temperature for 24 h. DMF (2 mL) and aqueous LiOH (2.5 M, 1 mL) were added and the reaction was concentrated to dryness under reduced pressure. The crude material was diluted with EtOAc and washed with H2O and brine. The aqueous layers were backextracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100% EtOAc (w/5% MeOH)/CH2Cl2) to afford methyl(2S,3R)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate (1.2 g, 100%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Product: COc1ccc(C(=O)NC[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1

Procedure:
64.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 4-methoxy-benzoic acid to give (R)-3-[(4-methoxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester. Yellow oil. MS 335.1 ([M+H]+)