Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH2:14][CH3:15].[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C)C1C=CN=CC=1.CCOC(C)=O>[C:16]([NH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH2:14][CH3:15])(=[O:18])[CH3:17]
Reactant: CCOC(=O)c1ccc(N)c(OCC)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(NC(C)=O)c(OCC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To a 100 mL round bottom flask were added ethyl 4-amino-3-ethoxybenzoate (1.3 g, 6.2 mmol), TEA (2.6 mL, 18.6 mmol), N,N-dimethylpyridin-4-amine (catalytic), acetic anhydride (0.88 mL, 9.3 mmol) and EtOAc (20 mL). The reaction mixture was stirred at ambient temperature for 3 hours and was then diluted with EtOAc (20 mL) and washed with 5% KOH (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified on a silica gel column eluting with a gradient of EtOAc/hexanes to give the title intermediate (1.1 g) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-])=O.O.C.[H][H]>NC1C=CC=CC=1.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc2c([N+](=O)[O-])cccc12
Reactant: [H][H]
Agent: [Pt]
Solvent: Nc1ccccc1
Solvent: O
Product: Nc1cccc2c(N)cccc12
Temperature: 18 °C

Procedure:
60 g (0.275 mol) of 1,5-dinitro naphthalene were suspended, in a 700 ml stirrer autoclave, in 340 ml of aniline and treated with 18 g of water-moist, 1%-strength catalyst of platinum and activated charcoal corresponding to 8 g of dry catalyst. Hydrogenation was carried out at 50° C. and a hydrogen pressure of 10 bars, as was described in Example 1. The hydrogen uptake was finished after 2 hours. The catalyst was separated off by filtration at 80° C. and the aniline subsequently removed by water-vapour distillation. The distillation residue was cooled to 18° C. and the precipitated crystallate filtered off and dried. In this way 40 g (92% of the theory) of 1,5-diamino naphthalene of m.p. 188°-189° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[C:3]=1[CH3:17].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[C:3]=1[CH2:17][Br:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Br)cc(Br)nc1-c1ccc(F)cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2nc(Br)cc(Br)c2CBr)c(F)c1
Temperature: 0 °C

Procedure:
To a stirred solution of 4,6-dibromo-2-(2,4-difluorophenyl)-3-methylpyridine (5.0 g, 13.77 mmol, 1 eq) in CCl4 (125 mL) was added N-bromosuccinimide (2.95 g, 16.6 mmol 1.2 eq) and benzoyl peroxide (340 mg, 1.37 mmol, 0.1 eq). The mixture was brought to and maintained at reflux until all the starting material was consumed (approx 3.5 h). The reaction mixture was cooled to 0° C. and the succinimide was filtered off. The solvent was removed under reduced pressure and the product was purified by flash column chromatography on silica gel elufing with 2% Et2O in hexanes giving 4,6-dibromo-3-(bromomethyl)-2-(2,4-difluorophenyl)pyridine. Mass spectrum (ESI) 440.1 (M+1); 442.1 (M+3); 444.1 (M+5); 446.1 (M+7). 1H NMR (500 MHz, CDCl3) δCHCl3: 7.84 (1H, s); 7.50 (1H, m); 7.05 (1H, m); 6.96 (1H, m); 4.44 (2H br s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([OH:10])=[O:9]>[Pd].O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)C=Cc1cccs1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCc1cccs1
Reaction time: 24 h
Yield: 59.7 %

Procedure:
Palladium on carbon (10%, 4.2 g) was added in one portion to a solution of 3-(2-thienyl)acrylic acid (15.59 g, 0.10 mol) in tetrahydrofuran (130 mL). The mixture was subjected to Parr hydrogenation conditions (45 psi, room temperature) for about 24 hours. Following filtration through Celite, the filtrate was concentrated down to dryness and gave a brown-colored solid which was recrystallized from water. There was isolated 9.32 g (60%) of the title compound as a mixture of white and tan colored needles, m.p. 58°-60° C. (m.p. lit. 62°-62.5° C.); 1H NMR (CD3SOCD3) 6 12.2 (br s, 1H), 7.23-7.21 (m, 1H), 6.89-6.86 (m, 1H), 6.82-6.81 (m, 1H), 2.99 (t, J=7.4 Hz, 2H), 2.53 (t, J=7.4 Hz, 2H); 13C NMR (CD3SOCD3) ppm 173.42, 143.39, 126.90, 124.70, 123.72, 35.61, 24.70; IR (KBr, cm-1) 3102-3036, 2922, 2644, 1706, 1440, 1408, 1310, 1232, 1220, 938, 848, 828, 714, 692; MS m/z (MH+) 157.
Reaction SMILES: O=CC[C@H](N[C:12]([CH:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:24])C.[Na+].C(N(CC)CC)C>ClCCCl>[F:20][C:17]1([F:21])[CH2:18][CH2:19][CH:14]([C:12]([OH:13])=[O:24])[CH2:15][CH2:16]1
Reactant: O=CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(O)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 148.1 %

Procedure:
To 21.1 mg (0.072 mmol) of 1-methyl-3-(tetrahydropyran-4-ylmethyl)-bicyclo[3.2.1]-1β,3,8-triaza-spiro[4.5]dodecan-2-one in 1.5 mL of DCE was added 21.2 mg (0.072 mmol, 1 eq.) of 4,4-difluoro-cyclohexanecarboxylic acid ((S)-3-oxo-1-phenyl-propyl)-amide, 19 mg (0.09 mmol, 1.25 eq.) of sodium triacetoxyborohydride and 12 μL (0.086 mmol, 1.2 eq.) of triethylamine. The reaction mixture was stirred overnight at room temperature and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (DCM/MeOH: 0 to 100) and redissolved in 1 mL of methanol and 100 μL of HCl (1N). The solution was then concentrated in vacuo and diluted with 2 mL of water to give after lyophilization 17.5 mg (40%) of 4,4-difluoro-cyclohexanecarboxylic acid {(S)-3-[1-methyl-3-(tetrahydropyran-4-ylmethyl)-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-spiro[4.5]dodec-8-yl]-1-phenyl-propyl}-amide hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[C:4]([CH2:16][CH3:17])[N:3]=1.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=2)=[C:4]([CH2:16][CH3:17])[N:3]=1
Reactant: CCc1nc(N)nc(N)c1-c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCc1nc(N)nc(N)c1-c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
In this method, commercially available 2,4-diamino-6-ethyl-5-(4-chlorophenyl)pyrimidine is nitrated with 70% nitric acid and concentrated sulfuric acid, yielding the corresponding 2,4-diamino-6-ethyl-5-(4-chloro-3-nitrophenyl)pyrimidine. The thus-prepared nitrophenylpyrimidine is in turn reduced with stannous chloride dihydrate in 10M hydrochloric acid, yielding the corresponding 2,4-diamino-6-ethyl-5-(3-amino-4-chlorophenyl)pyrimidine. The aminophenylpyrimidine may then be treated with an appropriate acid chloride in the presence of a base in tetrahydrofuran, yielding the desired 2,4-diamino-6-ethyl-5-[3-(substituted-carbonylamino)-4-chlorophenyl]pyrimidine (wherein W is --NHC(O)R4). These compounds may optionally be reduced with 1M boron-tetrahydrofuran complex in tetrahydrofuran, affording 2,4-diamino-6-ethyl-5-[3-(substituted-amino)-4-chlorophenyl]pyrimidine (wherein W is --NHR5).
Reaction SMILES: O.O.Cl[Sn]Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([N+:27]([O-])=O)[CH:20]=2)=[CH:17][CH3:18])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([NH2:27])[CH:20]=2)=[CH:17][CH3:18])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: CC=C(c1cc(OC)cc(OC)c1)c1ccc(OC)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC=C(c1cc(OC)cc(OC)c1)c1ccc(OC)c(N)c1
Temperature: 70 °C
Yield: 66.8 %

Procedure:
SnCl2.2H2O (5.20 g, 23.0 mmol) was added to a stirred solution of (E/Z) 4-[1-(3,5-dimethoxy-phenyl)-propenyl]-1-methoxy-2-nitro-benzene (1.10 g, 3.2 mmol) in ethanol (200 proof, 20 mL) and ethyl acetate (10 mL). The reaction mixture was heated at 70° C. for 1 h. The solution was cooled down to room temperature, poured into ice water (100 mL), and basified with 10 N NaOH (20 mL) to pH ˜12. The aqueous layer was extracted with ethyl acetate (5×35 mL). The combined organic layers were washed with water (60 mL), brine (50 mL) and dried (MgSO4). Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 5-[1-(3,5-dimethoxy-phenyl)-propenyl]-2-methoxy-phenylamine as an oil (0.64 g, 51% yield): 1H NMR (CDCl3) δ 1.70-1.78 (2d, J=7.0 Hz, 6H, 2CH3), 3.74-3.87 (4s+m, 22H, 6OCH3+2NH2), 6.02-6.10 (m, 2H, 2CH), 6.33-6.79 (m, 12H, Ar); 13C NMR (CDCl3) δ 15.60, 15.73, 55.30, 55.45, 55.52, 98.70, 98.92, 105.72, 107.99, 109.95, 109.99, 113.91, 116.77, 117.30, 120.32, 122.05, 123.83, 132.49, 135.56, 135.61, 142.09, 142.33, 142.50, 145.66, 146.32, 146.56, 160.36, 160.51; Anal. Calcd for C18H21NO3: C, 72.22; H, 7.07; N, 4.68. Found: C, 71.94; H, 7.37; N, 4.54.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH:22]([CH3:24])[CH3:23])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].[CH2:32](I)[CH2:33][CH3:34]>O>[CH:22]([N:3]1[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=[C:2]1[NH:1][CH2:32][CH2:33][CH3:34])([CH3:24])[CH3:23]
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C(C)C)c(=O)c23)c(C)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNc1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)n1C(C)C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a solution of 2-amino-3-isopropyl-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (100 mg, 0.31 mmol) and N,N-dimethylformamide (3 ml) was added sodium hydride (60% in oil, 40 mg, 1.0 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of n-PrI (170 mg, 1.0 mmol) and N,N-dimethylformamide (2 ml) at 0° C. and stirred for 0.5 hour. After stirring at 50° C. for 3 hours, the mixture was cooled and diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (20:1) to give 68 mg (60%) of the title compound.
Reaction SMILES: [C:1]1(=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)[Cl:28].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[C:1]1(=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([Cl:28])=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (2E)-3-{4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoic acid (11) (0.3 g, 0.861 mmol) and dry CH2Cl2 (5 mL) was added oxalyl chloride (0.15 mL, 1.72 mmol) slowly, followed by DMF (2 drops). The reaction mixture became a clear solution immediately after the addition of DMF. The reaction mixture was stirred at room temperature for 2 h under nitrogen. The reaction mixture was concentrated to give 39 as an oily residue that was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ 1.53 (s, 8H), 2.21-2.25 (m, 4H), 6.48 (d, J=16 Hz, 1H), 7.19 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.54 (d, J=16 Hz, 1H), 7.62 (d, J=8.1 Hz, 2H), 9.35 (s, 1H).
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])(=[O:8])=[O:7])(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])(=[O:8])=[O:7]
Reactant: CN(C)C(=O)c1c(S(=O)(=O)NC(C)(C)C)ccn1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1c(S(N)(=O)=O)ccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
To a solution of 5.63 g of 3-[[(1,1-dimethylethyl)amino]sulfonyl]-N,N,1-trimethyl-1H-pyrrole-2-carboxamide in 75 mL of methylene chloride was added 75 mL of TFA. The reaction mixture was allowed to stir at room temperature overnight ca. 16 hours. The reaction mixture was concentrated in vacuo. Three portions of diethyl ether were added to the residue and removed by evaporation to remove residual TFA, affording 4.21 g of the title compound as a gray solid, m.p. 185°-190.5° C.
Reaction SMILES: [CH2:1]([C:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])[CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)[CH:2]=C.[O:31]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:7]2[CH2:6][CH2:5][C:4]([CH2:1][CH2:2][OH:31])([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:9][C:8]2=[O:10])[CH:12]=1
Reactant: C=CCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1OC(CCO)(c2ccccc2)CCN1c1cccc(-c2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A solution of 6-allyl-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (600 mg, 1.47 mmol) in dry CH2Cl2 (10 mL) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to remove excess ozone. NaBH4 (450 mg, 11.7 mmol) was added to the mixture in portions at −20° C. The mixture was stirred overnight at rt. The mixture was quenched with water and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (150 mg, 25%). 1H NMR (400 MHz, CDCl3): δ=2.12-2.35 (m, 2H), 2.51 (m, 2H), 3.26 (m, 1H), 3.47-3.6 (m, 2H), 4.25 (m, 1H), 6.83 (m, 2H), 7.06 (m, 1H), 7.26-7.51 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([O:25]CC)=O)[O:20][N:19]=2)=[CH:4][CH:3]=1.[NH2:28][NH2:29].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([NH:28][NH2:29])=[O:25])[O:20][N:19]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
To a solution of ethyl 3-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate (10.5 mmol, 4.0 g) in MeOH (50 mL) was cooled to 0° C., and 99% NH2NH2.H2O (62.8 mmol, 3.2 g) was then added dropwise. In the period of addition, lots of white precipitate was generated, kept stirring for 15 mins, the white solid was collected by filtration. The white solid was dispersed into MeOH again, sonicated for 10 mins, filtered, to give the final product (3.3 g, 86.0%). m/e+=369 (M+H+). 1H NMR (400 MHz, in DMSO-d6): δ 10.9-10.5 (1H, D, brd, NH), δ 8.44-8.42 (1H, D, d, J=6.8 Hz, ArH), δ 7.87-7.85 (2H, D, dd, J=6.4, 1.6 Hz, ArH), δ 7.67-7.64 (1H, D, d, J=9.2 Hz, ArH), δ 7.56-7.54 (2H, D, dd, J=6.4, 1.6 Hz, ArH), δ 7.38-7.25 (1H, D, m, ArH), δ 5.01-4.75 (2H, D, brd, NH2), δ 4.75 (2H, D, s, CH2).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]1([CH2:27][C:28]([OH:30])=O)[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([OH:26])=O)[CH:18]=1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:24](=[O:26])[CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:27][C:28]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:30])[CH:18]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)Cc1cccc(CC(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)c1
Yield: 82.8 %

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 800 mg (4.1 mmol) 1,3-phenylenediacetic acid afforded, after flash chromatography (EtOAc), 1.93 g (84%) of the title compound as a colorless oil. MS m/e (%): 586 (M+NH4+, 100), 569 (M+H+, 60).
Reaction SMILES: ClCCOC1C=C(C=CC=1)C#N.Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].N1C=NC(S)=N1.[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1>>[N:32]1([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])[CH:36]=[CH:35][N:34]=[CH:33]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1cccc(OCCCCl)c1
Agent: N#Cc1cccc(OCCCl)c1
Agent: Sc1nc[nH]n1
Product: N#Cc1cccc(OCCCn2ccnc2)c1

Procedure:
By a method similar to that in Reference Example 2, and using, instead of 3-[(2-chloroethyl)oxy]benzonitrile, 3-[(3-chloropropyl)oxy]benzonitrile obtained in Reference Example 4 and using, instead of 1H-1,2,4-triazole-3-thiol, 1H-imidazole, the title compound was obtained as a colorless oil (1.65 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][CH:5]=1.[Br:13][C:14]1[C:19]([Cl:20])=[CH:18][C:17]([OH:21])=[C:16]([Cl:22])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CC1C=CC=CC=1C.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([O:21][C:17]2[CH:18]=[C:19]([Cl:20])[C:14]([Br:13])=[CH:15][C:16]=2[Cl:22])=[CH:8][C:7]([CH3:11])=[N:6][CH:5]=1
Reactant: Oc1cc(Cl)c(Br)cc1Cl
Reactant: COC(=O)c1cnc(C)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cnc(C)cc1Oc1cc(Cl)c(Br)cc1Cl
Temperature: 120 °C
Reaction time: 20 h
Yield: 7.6 %

Procedure:
To a solution of 1.25 g (6.734 mmol) 4-chloro-6-methyl-nicotinic acid methyl ester (commercially available, CAS RN 886372-05-0) in 30 mL o-xylene was added 1.792 g (7.408 mmol) 4-bromo-2,5-dichlorophenol (commercially available, CAS RN 1940-42-7), 0.502 g (1.347 mmol) tetrakis(acetonitrile)copper (I) hexafluorophosphate (commercially available, CAS RN 64443-05-6) and 5.536 g (16.836 mmol) cesium carbonate. The reaction mixture was stirred at 120° C. for 20 hours and was then allowed to cool to room temperature. Ethyl acetate (50 mL) and water (50 mL) was added and stirring was continued for another 10 minutes. The reaction mixture was filtered over Dicalite® speed plus (Acros) and the layers were separated. The aqueous layer was extracted with 200 mL ethyl acetate and the combined organic layers were washed with 200 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (50 g silica gel column, CombiFlash Companion, Isco Inc.) and a gradient of n-heptane:ethyl acetate (100:0 to 40:60) to give 200 mg (8%) of the title compound as a light yellow solid. MS (Turbo Spray): m/z=391.9 [M+H]+.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:5]([CH3:13])[C:6]2[C:7]([N:12]=1)=[N:8][CH:9]=[CH:10][CH:11]=2.[CH2:14]([N:16]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:18]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[C:17]1=[O:32])[CH3:15].[Cl-].[Cl-].[Ca+2].Cl>CN(C=O)C>[CH2:14]([N:16]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:18]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:4]3[N:5]([CH3:13])[C:6]4[C:7]([N:12]=3)=[N:8][CH:9]=[CH:10][CH:11]=4)=[CH:29][CH:30]=2)[C:17]1=[O:32])[CH3:15]
Reactant: Cn1c(Cl)nc2ncccc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ncccc4n3C)cc2)c2ncccc21
Yield: 65.2 %

Procedure:
The mixture of sodium hydride (14.32 mg), 2-chloro-1-methyl-1H-imidazo[4,5-b]pyridine (100 mg) and 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (152 mg) in DMF (3 mL) was stirred at 180° C. under a dry atmosphere (CaCl2 tube) for 20 min. The mixture was neutralized with 1N HCl at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 1-ethyl-3-{4-[(1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (150 mg) as white crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1.[NH2:25][C:26]1[C:27]([Cl:46])=[C:28]([N:34]2[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:36]([OH:45])[CH2:35]2)[CH:29]=[C:30]([C:32]#[N:33])[CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C([O-])(=O)C.[Pd+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:46][C:27]1[C:26]([NH:25][C:2]2[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:5]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]3[N:3]=2)=[CH:31][C:30]([C:32]#[N:33])=[CH:29][C:28]=1[N:34]1[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:36]([OH:45])[CH2:35]1
Reactant: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Agent: [Pd+2]
Agent: [Pd+]
Agent: CC(=O)[O-]
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
(328F1): A 1 liter round bottom flask was loaded with 2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (12.05 g, 35.2 mmol, Intermediate 10), methyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carbamate (10.9 g, 28.5 mmol), Pd(OAc)2 (377 mg, 1.679 mmol), XANTPHOS (990 mg, 1.711 mmol) and Potassium phosphate (17.1 g, 81 mmol). The vial was evacuated and back-filled with nitrogen 4 times. Toluene (320 mL) was added and the flask was again evacuated and back-filled with nitrogen 4 times, and then heated with stirring to 90° C. for 16 hours. LCMS shows product and both starting materials as separate peaks. (˜5:1:1 ratio by UV). The flask was opened under nitrogen, additional palladium(I) acetate (190 mg, 0.846 mmol), XANTPHOS (500 mg, 0.864 mmol) and potassium phosphate tribasic (7.5 g, 35.3 mmol) were added and the flask re-sealed, flushed with nitrogen again and heating continued for additional 6 hours. Celite was added to the reaction mixture. The suspension was stirred briefly, and then filtered through a layer of Celite. Solids were washed with DCM. The filtrate was concentrated to brown foam. (23.9 g). Purification by column chromatography on silica (1500 g) using a gradient from 100% CH2Cl2 to (50% EtOAc+50% CH2Cl2) gave methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (11.2 g).