Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]#[CH:22])[C:17](O)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]#[CH:22])[C:17]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=3)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: C#CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: C#CCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
295 mg (purity 85%, 0.70 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]pent-4-ynoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 91 mg (24% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[CH2:13]([O:15][C:16]1[N:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24])[CH3:14].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:22][C:19]2[CH:20]=[N:21][C:16]([O:15][CH2:13][CH3:14])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:18]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: CCOc1ncc(N)cc1C(F)(F)F
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOc1ncc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (90 mg, 0.386 mmol) in DCM (10 mL) was added 6-ethoxy-5-(trifluoromethyl)pyridin-3-amine (88 mg, 0.425 mmol), DIEA (0.135 mL, 0.772 mmol) and HATU (220 mg, 0.579 mmol). The mixture was stirred at 25° C. for 16 h. The mixture was diluted with H2O and extracted with DCM. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=1:1, Rf=0.6) to yield a light yellow oil of 2-(4-bromo-2-fluorophenyl)-N-(6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)acetamide (120 mg, 0.228 mmol, 59.0% yield): 1H NMR (400 MHz, CD3OD) δ 8.49 (d, J=2.0 Hz, 1H), 8.27 (d, J=2.5 Hz, 1H), 7.39-7.34 (m, 3H), 4.47 (m, 2H), 1.21 (t, J=6.5 Hz, 3H); ES-LCMS m/z 421.0 (M+H).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH:5]=[C:6]([CH3:8])[CH3:7])[CH3:3].[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O.C(Cl)CCC>[CH3:16][CH2:15][O:14][C:12]([CH:11]1[C:6]([CH3:8])([CH3:7])[CH:5]1[CH:4]=[C:2]([CH3:3])[CH3:1])=[O:13]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)=CC=C(C)C
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCCCCl
Product: CCOC(=O)C1C(C=C(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
18.05 mg (0.05 mmol) of copper trifluoromethanesulfonate, 19.9 mg (0.055 mmol) of bis[2-[4(R)-phenyl-5,5-dimethyl-2-oxazoline]]methane and 5 ml of n-butyl chloride were charged in a 50 ml Schienk's tube wherein the atmosphere is substituted with nitrogen, followed by stirring at room temperature for 10 minutes. After 30.0 g (275 mmol) of 2,5-dimethyl-2,4-hexadiene was further added, 5.70 g (50 mmol) of ethyl diazoacetate was added dropwise at 50° C. over 2 hours. After the completion of the dropwise addition of ethyl diazoacetate, the mixture was further stirred at 50° C. for 1 hour. The amount of chrysanthemic acid ethyl ester formed was determined by gas chromatography. As a result, it was 8.43 g and the yield was 86.0% based on ethyl diazoacetate and, furthermore, the trans/cis ratio was 72/28. After 2,5-dimethyl-2,4-hexadiene (boiling point: 51° C./30 mmHg) was distilled off from the reaction mixture, 1 g of the concentrated solution was taken out. Then, 10 ml of an aqueous 1N sodium hydroxide solution and 5 ml of ethanol were added and alkali hydrolysis was performed by stirring at 100° C. for 1 hour. The resulting chrysanthemic acid was reacted with I-menthol and the formed diastereomer ester was analyzed by gas chromatography. As a result, the optical purity of the (+)-trans isomer was 60% e.e., whereas, the optical purity of the (+)-cis isomer was 27% e.e.
Reaction SMILES: C1[O:3]C1.[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16](O)=[CH:17][CH:18]=1>>[CH2:12]([C:13]1([OH:3])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: C1CO1
Reactant: CCCCCCCCCc1ccc(O)cc1
Product: CCCCCCCCCC1(O)CCCCC1

Procedure:
The same procedures as the first ethylene oxide addition step of Example 29 were carried out except that the amount of ethylene oxide was changed to 61 g (1.38 moles). That is, 0.69 mole of ethylene oxide was reacted with 1 mole of nonylphenol. Colorless liquid thus obtained was analyzed with liquid chromatography. The liquid contained 27.3% by weight of nonylphenol, 72.7% by weight of one molar ethylene oxide adduct, and trace amount of two molar ethylene oxide adduct of nonylphenol, respectively. The reaction product unfavorably formed a large amount of nonylcyclohexanol in the next hydrogenation step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28].O>C(Cl)Cl>[CH3:18][N:14]1[C:15]2[C:10](=[CH:9][C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH:7]=[N:6][CH:5]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:12][C:13]1=[O:19]
Reactant: CN1C(=O)CCc2cc(-c3cncc(N)c3)ccc21
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCS(=O)(=O)Nc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
To a solution of 6-(5-amino-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (intermediate A-2, 0.02 g, 0.079 mmol) in DCM (0.5 mL) was added triethylamine (0.024 g, 0.237 mmol) followed by ethanesulfonyl chloride (0.01 g, 0.079 mmol) and the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM, poured into water (5 mL) and the aqueous layer was extracted with DCM (2×20 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH-DCM gradient to give the title compound (0.007 g, 23%) as a brown solid. MS: 346.0 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[CH3:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:22])[CH:28]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: Cc1cccc(B(O)O)c1
Product: COc1ccc(-c2nc3cc(-c4cccc(C)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-methylphenylboronic acid (117 mg, 0.86 mmol) the subtitle compound was obtained, (69 mg, 33%). 1H NMR (DMSO) δ 8.64(d, 1H), 847(dd, 1H), 8.14(d, 1H), 7.86(d, 1H), 7.72(dd, 1H), 7.64(d, 1H), 7.55(m, 2H), 7.39(t, 1H), 7.22(d, 1H), 4.07(s, 1H), 2.40(s, 3H).
Reaction SMILES: C([O:8][C:9](/[CH:11]=[CH:12]/[C:13]1[N:14]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:15]=[CH:16][CH:17]=1)=[O:10])C1C=CC=CC=1>[Pd].CO>[C:9]([CH2:11][CH2:12][C:13]1[N:14]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:15]=[CH:16][CH:17]=1)([OH:10])=[O:8]
Reactant: COC(=O)c1cccc(-n2cccc2/C=C/C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(-n2cccc2CCC(=O)O)c1
Yield: 54 %

Procedure:
10% Palladium on carbon (0.25 g) was added to the solution of methyl 3-[2-((E)-2-benzyloxycarbonylethenyl)pyrrol-1-yl]benzoate (2.5 g) in methanol (50 ml) and the mixture was subjected to catalytic reduction at the ambient temperature under atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with diisopropyl ether to give methyl 3-[2-(2-carboxyethyl)pyrrol-1-yl]benzoate (1.02 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2]CC.[C:19]([O:22][CH2:23][CH2:24][CH2:25]Br)(=[O:21])[CH3:20]>>[CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:16]([O:17][CH2:25][CH2:24][CH2:23][O:22][C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])[CH3:2]
Reactant: CCCCOc1c(O)c2cccc(O)c2oc1=O
Reactant: CC(=O)OCCCBr
Product: CCOc1c(O)c2cccc(OCCCOC(C)=O)c2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-butoxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 3-bromopropyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-ethoxy-4-hydroxy-8-(3-acetoxypropyloxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([CH3:22])[C:14]=1[CH3:23]>CN(C=O)C.[NH4+].[Cl-].C(#N)C>[CH3:23][C:14]1[C:15]([CH3:22])=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=1[O:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1C
Reactant: Nc1cc(CO)ccn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1c(OCc2ccnc(N)c2)ccc([N+](=O)[O-])c1C
Temperature: 0 °C

Procedure:
To a stirred solution of (2-aminopyridin-4-yl)methanol (1.33 g, 10.8 mmol) in DMF (10 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 537 mg, 13.4 mmol) and the reaction mixture maintained at 0° C. for 5 min and then warmed to RT for 1 hr. The mixture was re-cooled to 0° C., treated with a solution of 1-fluoro-2,3-dimethyl-4-nitrobenzene (2.00 g, 12.0 mmol) in DMF (5.0 mL) and after 2 min was warmed to RT. After 20 hr the reaction mixture was diluted with saturated aq. NH4Cl (50 mL) and extracted with EtOAc (2×100 mL) and then ether (100 mL). The combined organic extracts were dried and evaporated in vacuo to afford a red oil. The residue was diluted with acetonitrile (50 mL), upon which a brown precipitate formed. The precipitate was removed by filtration and the filtrate was evaporated in vacuo. This residue was purified by flash column chromatography (SiO2, 80 g, MeOH in DCM, 0-5%, gradient elution) to afford the title compound, Intermediate C3, as a yellow solid (1.19 g, 39%); Rt 1.35 (Method 2); m/z 274 (M+H)+ (ES+).
Reaction SMILES: [NH2:1]/[C:2](/[CH2:10][F:11])=[C:3](/[F:9])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[Cl:14][C:15]1[CH:26]=[C:25]([F:27])[C:24]([N:28]=[C:29]=[O:30])=[CH:23][C:16]=1[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18]>CN(C)C=O>[Cl:14][C:15]1[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:29]([NH:1][C:2]([CH2:10][F:11])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[F:9])=[O:30])=[CH:23][C:16]=1[C:17]([O:19][CH:20]([CH3:21])[CH3:22])=[O:18]
Reactant: CCOC(=O)/C(F)=C(\N)CF
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)=C(CF)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Reaction time: 0.25 h

Procedure:
A solution of 1.80 g of ethyl 3-amino-2,4-difluorocrotonate in 20 ml of absolute dimethylformamide is added dropwise with stirring during 10 minutes to 0.48 g of a 55% sodium hydride dispersion in 25 ml of dimethylformamide at room temperature, and the mixture is stirred for a further 15 minutes. Thereafter 2.81 g of isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate are added, with the result that the temperature of the reaction mixture rises to 35° C. Then the mixture is stirred for a further two hours at room temperature. The isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-2-fluoro-1-fluoromethyl-vinyl]ureido}-benzoate formed as an intermediate is not isolated.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=5)=[C:35]([CH3:49])[CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39]([CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=5)=[O:59])=[C:35]([CH3:49])[CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCC)c(C)c2)CCCN3CC(C)C)cc1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)c(C)c2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[[1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (370 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloro-per-benzoic acid (144 mg) in dichloromethane (10 ml) at −78° C. After stirring as such for 1 hour, the dry ice-acetone bath was removed, and an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and saturated brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified with basic silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:40) and recrystallized from hexane-ethyl acetate to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[[1-propylimidazol-5-yl)methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (289 mg) as yellow crystals (Compound 39).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[CH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].CI.[Cl-].[NH4+]>CCCCCC.O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[CH2:18][CH:19]([CH3:1])[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]
Reactant: O=C(CCC1OCCO1)c1ccccc1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(CC1OCCO1)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A 1.6N solution of n-butyllithium in n-hexane was added dropwise within 15 minutes at -70° C. under argon and while stirring to a solution of 7.1 ml of diisopropylamine in 200 ml of absolute tetrahydrofuran. The reaction mixture was stirred at 0° C. for 15 minutes, then again cooled to -70° C., treated with 30 ml of hexamethylphosphoric acid triamide and 9.5 g of 3-(1,3-dioxolan-2-yl)propiophenone, dissolved in 10 ml of absolute tetrahydrofuran and stirred for 15 minutes. After the addition of 3.2 ml of methyl iodide at -70° C. the mixture was brought to room temperature and stirred for 2 hours. The reaction solution was poured on to 100 ml of saturated ammonium chloride solution and extracted once with 200 ml of ethyl acetate and twice with 150 ml of ethyl acetate each time. The organic phases were washed with 100 ml of water, combined, dried with MgSO4 and filtered. The filtrate was concentrated and the residue, 23.4 g of brown oil, was chromatographed on 750 g of silica gel with hexane/ethyl acetate mixtures (4:1 to 2:1). 7.1 g (70%) of 3-(1,3-dioxolan-2-yl)-2-methylpropiophenone were isolated as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[N:9]=2)[C:5]([O:23][CH3:24])=[CH:4][N:3]=1.[C@H:25]1([NH2:32])[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1.[OH-].[K+]>O1CCOCC1>[NH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:32][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=4)[N:9]=3)[C:5]([O:23][CH3:24])=[CH:4][N:3]=2)[CH2:26][CH2:27]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: COc1cnc(Cl)cc1-c1cccc(NCc2cccc(F)c2)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cnc(N[C@H]2CC[C@H](N)CC2)cc1-c1cccc(NCc2cccc(F)c2)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a scintillation vial was added 2′-chloro-N-(3-fluorobenzyl)-5′-methoxy-2,4′-bipyridin-6-amine (30 mg, 0.087 mmol), trans-cyclohexane-1,4-diamine (45 mg, 0.394 mmol), 1,3-bis(2,6-di-isopropylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium(0) (11.4 mg, 8.73 μmol), KOH (45 mg, 0.802 mmol) and Dioxane (0.3 mL). The resulting mixture was stirred at 100° C. for 18 h. The mixture was concentrated in vacuo and then diluted with water. The resultant solid was filtered and washed with water (×3). The solid was then purified by reverse phase preparative HPLC and then lyophallized to yield N2′-(trans-4-aminocyclohexyl)-N6-(3-fluorobenzyl)-5′-methoxy-2,4′-bipyridine-2′,6-diamine (6.5 mg), LCMS (m/z): 422.3 (MH+), retention time=0.54 min as a TFA salt. 1H-NMR (400 MHz, METHANOL-d4, 25° C.) 1.40-1.66 (m, 4H) 2.05-2.25 (m, 4H) 3.10-3.25 (m, 1H) 3.55-3.64 (m, 1H) 3.86 (s, 3H) 4.57 (s, 2H) 6.69 (d, J=8.4 Hz, 1H) 6.92-7.00 (m, 1H) 7.10 (d, J=10.0 Hz, 1H) 7.17 (d, J=7.6 Hz, 1H) 7.28-7.33 (m, 2H) 7.48-7.52 (m, 2H) 7.53-7.58 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20]C(OC(C)(C)C)=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[N+](C1C=CC(O[C:40]([O:42][CH2:43][C:44]2[S:48][CH:47]=[N:46][CH:45]=2)=[O:41])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+].O.N.Cl>C(OCC)(=O)C.O>[NH2:20][C@@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][C@H:10]([OH:28])[C@@H:2]([NH:1][C:40]([O:42][CH2:43][C:44]1[S:48][CH:47]=[N:46][CH:45]=1)=[O:41])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: N
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Product: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 30 °C
Reaction time: 2.5 h

Procedure:
To a 750 gallon glass lined reactor were charged (2S, 3S, 5S)-2-Amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane--0.5succinic acid salt (75.0 kg, 169 moles), 5-(p-nitrophenyloxycarbonyloxymethyl)thiazole hydrochloride (65.0 kg, 205 moles) and sodium bicarbonate (70.0 kg, 833 moles). Ethyl acetate (826 kg, 918 L) was added and the agitator was started. Tap water (788 kg) was added and the mixture was warmed to 30° C. and stirred for 2.5 hours until all of the solids were dissolved. After settling for 30 minutes, the aqueous layer was separated and discarded. The organic layer was warmed to 60° C. and stirred for 12 hours. The solution was then cooled to 30° C. and 28% ammonia water (9.0 kg, 148 moles) was added. The mixture was stirred for 3 hours at 25°-30° C. The mixture was washed three times with aqueous 10% potassium carbonate solution (903 kg each time). The aqueous layers were drained and discarded after each wash. Concentrated hydrochloric acid (59.0 kg, 600 moles) was added to the ethyl acetate solution and warmed to 50° C. with stirring for 3 hours.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]#[C:12]Cl)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].C(O)(=O)C>O1CCCC1.[Cu]>[CH3:1][O:2][C:3]([C:5]1([C:11]#[CH:12])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(C#CCl)CCOCC1
Agent: [Cu]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C#CC1(C(=O)OC)CCOCC1
Temperature: 60 °C

Procedure:
4-Chloroethynyl-tetrahydro-pyran-4-carboxylic acid methyl ester (1.01 g, 5 mmol) and copper powder (1.6 g, 25 mmol) were suspended in tetrahydrofuran (100 mL). Acetic acid (15 mL) was added and the reaction mixture was heated to 60° C. for 3 hours. After this time, the reaction mixture was poured onto water (copper powder was filtered off with the use of the filtration paper) and extracted with diethyl ether (3×50 mL). The combined organic extracts were washed with saturated solution of ammonium chloride (3×50 mL), with saturated solution of sodium bicarbonate (2×50 mL) and with water (50 mL). This water phase was extracted with diethyl ether (50 mL). Combined organic extracts were washed with brine (50 mL) and dried over magnesium sulfate, filtered through a 2 cm layer of silica gel (silica gel layer was washed with 50 mL of ethyl acetate), and concentrated under reduced pressure. After drying under high vacuum for one day, the title compound was isolated (0.84 g, quantitative yield) as a colorless oil. Rf=0.37, 30% ethyl acetate in iso-hexanes, phosphomolybdic acid in ethanol. LCMS (m/z) 169.0 [M+H]′ Tr=2.43 min (Gemini 5u C18 110 Å, 50×4.60 mm 5 micron column, 3.5 min, 2 ml/min, 5-100% acetonitrile/water, 0.1% acetic acid modifier gradient). 1H NMR (400 MHz, CDCl3): δ 3.80-3.67 (m, 4H), 3.73 (s, 3H), 2.34 (s, 1H), 1.98 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.Br[CH2:33][CH2:34][CH2:35][C:36](OCC)=[O:37].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[N:26]1([C:24]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:10]3[N:9]=[C:8]([N:4]4[CH2:5][CH2:6][CH2:7][C@@H:2]([N:1]5[CH2:33][CH2:34][CH2:35][C:36]5=[O:37])[CH2:3]4)[CH:16]=[CH:15][C:11]=3[C:12]([NH2:14])=[O:13])=[CH:23][CH:22]=2)=[O:25])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: CCOC(=O)CCCBr
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N2CCC[C@@H](N3CCCC3=O)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 100 °C
Yield: 28 %

Procedure:
A solution of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (80 mg) and ethyl 4-bromobutanoate (37 mg, 1 eq.) in DMF (1 mL) was treated with Cs2CO3 (184 mg, 3 eq) and heated at 100° C. for 2 days. The reaction mixture was diluted with ethyl acetate, washed with water, 10% LiCl, and concentrated. The residue was purified by MPLC chromatography (ISCO, 7% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 26 mg of (R)-2-(4-(morpholine-4-carbonyl)phenylamino)-6-(3-(2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinamide as a light yellow solid. LCMS: (M+H)+=493.27. 1H NMR (500 MHz, CDCl3) δ ppm 11.18 (1H, s), 7.67 (2H, d, J=8.80 Hz), 7.53 (1H, d, J=8.80 Hz), 7.36 (2H, d, J=8.80 Hz), 6.06 (1H, d, J=8.80 Hz), 5.68 (2H, br. s.), 4.20-4.45 (2H, m), 3.98-4.19 (1H, m), 3.71 (8H, br. s.), 3.42-3.49 (1H, m), 3.33-3.41 (1H, m), 2.92-3.00 (1H, m), 2.83-2.91 (1H, m), 2.44 (2H, t, J=8.25 Hz), 2.05 (2H, qd, J=7.61, 7.42 Hz), 1.94 (1H, dd, J=11.82, 3.57 Hz), 1.81-1.89 (1H, m), 1.59-1.80 (2H, m).