Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C:10]([N:12]1[CH2:21][C@@H:18]2[C@H:19]([OH:20])[C@H:13]1[C@H:14]([O:17]2)[O:15][CH3:16])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C(Cl)Cl>[C:28]([O:20][C@H:19]1[C@H:18]2[CH2:21][N:12]([C:10]([O:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:11])[C@@H:13]1[C@H:14]([O:17]2)[O:15][CH3:16])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CO[C@H]1O[C@@H]2CN(C(=O)OC(=O)c3ccccc3)[C@H]1[C@H]2O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@H]1O[C@@H]2CN(C(=O)OC(=O)c3ccccc3)[C@H]1[C@H]2OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
Methyl N-benzoyloxycarbonyl-2,5-dideoxy-2,5-imino-α-D-lyxofuranoside (Tetrahedron, 1986, vol. 42, p. 5685-5692) (13.9 g, 49.8 mmol) was dissolved in methylene chloride (200 mL) and pyridine (20 mL, 249.0 mmol) and benzoyl chloride (11.6 mL, 99.6 mmol) were added thereto, followed by stirring of the mixture at room temperature for 2 hours. After 1N hydrochloric acid (200 mL) was added to the reaction mixture at 0° C. and the mixture was extracted with methylene chloride (100 mL), the organic layer was washed with saturated aqueous sodium hydrogencarbonate (200 mL) and saturated brine (200 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 5:1-3:1, V/V) to obtain the desired title compound (15.82 g, yield 83%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:17]N1C(=O)CCC1=O.C1(C(F)(F)F)C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>>[Br:17][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C#N)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: N#Cc1ccccc1-c1ccc(CBr)c(F)c1
Temperature: 78 °C
Reaction time: 16 h

Procedure:
To a mixture of 3′-fluoro-4′-methylbiphenyl-2-carbonitrile (110 g), N-bromosuccinimide (97.3 g) and benzotrifluoride (1.0 L) was added azobisisobutyronitrile (1.71 g), and the mixture was heated to an internal temperature of 78° C. and stirred for 16 hr. The reaction mixture was cooled to around 40° C., and the insoluble material was removed to give a solution of 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile in benzotrifluoride. To a suspension of sodium hydride (60% in oil, 25 g) in tetrahydrofuran (750 mL) was added dropwise a solution of ethyl 3-oxohexanoate (164 g) in tetrahydrofuran (250 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hr, and a solution of 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile in benzotrifluoride above mentioned was added at 0° C. The reaction mixture was further stirred at room temperature for 16 hr, and added to 1 M hydrochloric acid (1.0 L), and the obtained mixture was concentrated under reduced pressure. The obtained mixture was extracted with ethyl acetate, and the obtained extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless oil (145 g, 76%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:24][CH2:23][CH2:22]1.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>CN(C=O)C>[N:21]1([C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[O:19][CH3:20])[CH2:24][CH2:23][CH2:22]1
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Reactant: C1CNC1
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: CN(C)C=O
Product: COc1cc(OCc2ccccc2)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(benzyloxy)-2-methoxyphenyl]acetic acid (1.8 g, 6.61 mmol) was dissolved in DMF (5 ml) and azetidine (0.566 g, 9.92 mmol), DIEA (3.46 ml, 19.8 mmol), and HATU (4.02 g, 10.6 mmol) added. The mixture was stirred at RT for 1 hr. The solution was loaded directly onto a Biotage RP C18 cartridge (30 g) and purified using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 312 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:10])([CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]#[N:4].Cl[N:12](Cl)[C:13]([CH3:21])([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]#[N:15].[OH-].[Na+]>O>[N:12]([C:13]([CH3:21])([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]#[N:15])=[N:1][C:2]([CH3:10])([CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]#[N:4]
Reactant: CC(C)CCC(C)(C#N)N(Cl)Cl
Reactant: CC(C)CCC(C)(N)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CCC(C)(C#N)N=NC(C)(C#N)CCC(C)C

Procedure:
30 g of 94% pure 2-amino-2,5-dimethylhexanenitrile is chlorinated in water at 1080 mv by the method of Example 2. To the resulting aqueous dispersion of 2-dichloroamino-2,5-dimethylhexanenitrile, following the method of Example 1, caustic soda, wetter, and a further 20 g of 2-amino-2,5-dimethylhexanenitrile are added and the suspension is filtered to yield 40.6 g of the title compound as a creamy white solid, mp 56°-58° C. (88%).
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21][C:22]1[C:27]([OH:28])=[C:26]([CH:29]=[O:30])[C:25]([CH2:31][OH:32])=[CH:24][N:23]=1.Cl.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][C:22]1[C:27]([OH:28])=[C:26]([CH:29]=[O:30])[C:25]([CH2:31][O:32][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:24][N:23]=1
Reactant: Cc1ncc(CO)c(C=O)c1O
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCc1cnc(C)c(O)c1C=O

Procedure:
A solution of z,z,z-octadeca-6,9,12-trienoyl chloride (800 mg, 2.7 mmol) in methylene chloride (10 ml) was added slowly dropwise to a mixture of pyridoxal hydrochloride (500 mg, 2.45 mmol), triethylamine (1 ml, 7.2 mmol) and 4-(N,N-dimethylamino)pyridine (few mg, catalytic amount) in methylene chloride (20 ml) at 0° C. under nitrogen. On completion, as indicated by tlc, the mixture was concentrated and purified by flash chromatography (ethyl acetate/hexane), yielding 2-methyl-3-hydroxy-4-formyl-5-(z,z,z-octadeca-6,9,12-trienoyloxy)methyl pyridine as a colourless oil which subsequently solidified.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH2:24]Br)=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][Mg+].[Br-]>CCOCC.[Cu]I>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH2:24][CH3:28])=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1c2ccc(-c3ccccc3)cc2C(CBr)=CC1(C)C
Reactant: C[Mg+]
Agent: [Cu]I
Agent: [Br-]
Solvent: CCOCC
Product: CCC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of N-tert-butyloxycarbonyl-4-bromomethyl-1,2-dihydro-2,2-dimethyl-6-phenylquinoline (structure 12, where R1=phenyl) (20 mg, 0.047 mmol) and copper (I) iodide (4 mg, 0.02 mmol) in 1 mL of anhydrous ether at 0° C. was added MeMgBr (0.060 mL, 3 M in ether). After 30 min of stirring at 0° C., the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to provide an oil which was purified by SGC (silica gel, hexane/ethyl acetate, 9:1) giving N-tert-butyloxycarbonyl-4-ethyl-1,2-dihydro-2,2-dimethyl-6-phenylquinoline (16 mg, 91%). 1H NMR (acetone-d6) 7.65 (d, J=8.7, 2H), 7.51 (dd, J=8.0, 1.7, 1H), 7.29 (m, 2H), 7.43 (m, 3H), 5.56 (s, 1H), 2.55 (q, J=8.9, 2H), 1.51 (s, 6H), 1.57 (s, 9H), 1.19 (t, J=8.9, 3H). To a solution of N-tert-butyloxycarbonyl-4-ethyl-1,2-dihydro-2,2-dimethyl-6-phenylquinoline (16 mg, 0.044 mmol) in 1 mL of dichloromethane at 0° C. was added 0.3 mL of trifluoroacetic acid. After 10 min of stirring, the reaction was quenched with saturated NaHCO3, and extracted with dichloromethane. The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to provide an oil that was purified by SGC (silica gel, hexane/ethyl acetate, 7:3) to provide 3 mg (25%) of Compound 112. Data for Compound 112: 1H NMR (acetone-d6) 7.55 (d, J=8.6, 2H), 7.37 (m, 3H), 7.23 (m, 2H), 6.59 (d, J=8.26, 1H), 5.38 (s, 1H), 3.76 (s, 1H), 2.48 (q, J=7.4, 2H), 1.29 (s, 6H), 1.17 (t, J=7.4, 3H).
Reaction SMILES: [F:1][C:2]([F:40])([CH2:6][NH:7][C:8]([NH:10][C@@:11]([C:26]1[CH:31]=[C:30]([O:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])[CH:29]=[C:28]([F:39])[CH:27]=1)([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])[C:3]([OH:5])=O.C(Cl)(=O)OCC.CC[N:49](CC)CC.N.O>C(Cl)Cl>[F:1][C:2]([F:40])([CH2:6][NH:7][C:8]([NH:10][C@@:11]([C:26]1[CH:31]=[C:30]([O:32][C:33]([F:37])([F:38])[CH:34]([F:35])[F:36])[CH:29]=[C:28]([F:39])[CH:27]=1)([C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])[C:3]([NH2:49])=[O:5]
Reactant: CCN(CC)CC
Reactant: O=C(NCC(F)(F)C(=O)O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: CCOC(=O)Cl
Agent: N
Solvent: O
Solvent: ClCCl
Product: NC(=O)C(F)(F)CNC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
To a solution of (R)-2,2-difluoro-3-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)propanoic acid (60 mg, 0.1 mmol) in CH2Cl2 (1 mL) at 0° C. was added ethyl carbonochloridate (10 uL, 0.1 mmol), followed by NEt3 (0.021 mL, 0.15 mmol) and NH3.H2O (0.1 mL, 2.6 mmol). The reaction mixture was stirred at rt for 30 min, then concentrated under reduced pressure and purified by prep HPLC (Phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to yield (R)-2,2-difluoro-3-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)propanamide as a white solid (12 mg, 21% yield). LCMS: RT=3.85 min [M+H] 576.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].FF.[Cl:11]Cl>Cl>[Cl:11][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: ClCl
Agent: Cl
Agent: FF
Product: O=c1[nH]cc(Cl)c(=O)[nH]1

Procedure:
In a suitable reaction vessel as in the previous examples a suspension of uracil (1.00g) in an aqueous solution of 18% HCl (10 ml, representing 5 ml of concentrated HCl and 5 ml of water) was introduced. Gaseous fluorine (0.024 moles) was bubbled through the suspension when the reaction temperature of 72°-80°C was reached. The reaction continued for about 140 minutes until the presence of fluorine was detected leaving the reaction vessel. The ratio of fluorine to uracil was 2.73. During the course of the reaction the odor of chlorine gas was observed. A white solid was present throughout the reaction and a final product of 0.98g was collected by filtration. Elemental analysis of the compound detected no fluorine and indicated the compound to be 5-chlorouracil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:11][C:12]1[N:13]=[N:14][C:15]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)=[CH:16][CH:17]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCc1ccc(Oc2ccc(Cl)nn2)cc1
Temperature: 110 °C
Yield: 56.6 %

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol (1.533 g, 11.09 mmol) in DMF (15 mL) was added 3,6-dichloropyridazine (1.574 g, 10.57 mmol) and K2CO3 (1.752 g, 12.68 mmol). The mixture was heated at 110° C. overnight. Purification via reverse phase flash chromatography then afforded the title compound (1.5 g, 5.98 mmol, 56.6% yield). LCMS: rt=2.23 min, [M+H+]=251
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].F[C:15]1[CH:20]=[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])[C:18]([F:34])=[CH:17][C:16]=1[N+:35]([O-:37])=[O:36].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[F:34][C:18]1[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:20][C:15]([O:1][C:2]2[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=2[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[C:16]([N+:35]([O-:37])=[O:36])[CH:17]=1
Reactant: COC(=O)COc1ccccc1O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
A mixture of 15.16 g of methyl (2-hydroxyphenoxy)acetate, 29.23 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene, 11.5 g of anhydrous potassium carbonate, and 160 ml of N,N-dimethylformamide was stirred at room temperature for 30 minutes and then at 70° C. for 3 hours. Another 5 g of methyl (2-hydroxyphenoxy)acetate was added, and the mixture was stirred for 1 hour. The reaction mixture was poured into 2% aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 17.8 g of methyl [2-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}phenoxy]acetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C-:19]#[N:20].[Na+]>C(#N)C.[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C>[C:19]([CH2:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][N:7]([CH3:8])[C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])#[N:20]
Reactant: [C-]#N
Reactant: CN(Cc1cccc(CBr)c1)C(=O)OC(C)(C)C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(Cc1cccc(CC#N)c1)C(=O)OC(C)(C)C

Procedure:
tert-Butyl-N-[3-(bromomethyl)benzyl]-N-methylcarbamate (preparation 13) (3.2 g, 10.18 mmol) was dissolved in acetonitrile (50 ml) and treated with sodium cyanide (1.23 g, 25.10 mmol) followed by benzyl triethylammonium bromide (220 mg, 0.8 mmol) and the resultant mixture stirred at room temperature for 4 days. The resultant slurry was diluted with ethyl acetate (200 ml) washed with water, sat aq brine and dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave a pale yellow solid which was purified by chromatography (SiO2, eluting with 100% CH2Cl2) to give the desired product with a trace of impurity (3.0 g). 1H NMR (CDCl3) δ 1.50 (s, 9H), 2.80 (s, b, 3H), 3.75 (s, 2H), 4.40 (s, 2H), 7.20 (m, 3H), 7.35 (t, 1H). LRMS m/z=278.1 (M+18)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:20])=[N:5][CH:6]=[C:7]([CH2:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[NH:12][CH:11]=2)[CH:8]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:30]=O)[C:25]([O:28][CH3:29])=[N:26][CH:27]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[F:21][C:22]1[CH:23]=[C:24]([CH2:30][NH:20][C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH2:9][C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=4)[NH:12][CH:11]=3)=[CH:6][N:5]=2)[C:25]([O:28][CH3:29])=[N:26][CH:27]=1
Reactant: COc1ncc(F)cc1C=O
Reactant: COc1cc(Cc2c[nH]c3ncc(C)cc23)cnc1N
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(Cc2c[nH]c3ncc(C)cc23)cnc1NCc1cc(F)cnc1OC
Temperature: 80 °C

Procedure:
To 3-methoxy-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (128, 1 equivalent) in 2 mL of acetonitrile, 5-fluoro-2-methoxy-pyridine-3-carbaldehyde (37, 1 equivalent), triethylsilane (5 equivalents) and trifluoroacetic acid (6.9 equivalents) are added. The reaction is heated at 80° C. for 18 hours, then concentrated under vacuum and mixed with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer is washed with water, brine, then dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CC1C2C(=CC=CC=2)C=CC=1.[C-]#N.[Na+].[CH2:28]([N:32]1C=CN=C1)CCC>[Cu]I.O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:28]#[N:32])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: CCCCn1ccnc1
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1cccc2ccccc12
Solvent: O
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C

Procedure:
A 100-mL, three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (99.1% purity, 5.0 g, 0.02 mol) and 1-methylnaphthalene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature, and sodium cyanide (ground to a powder just prior to use) (1.25 g, 0.024 mol, assuming 95% purity), copper(I) iodide (0.57 g, 0.003 mol, 98% purity) and 1-butyl-1H-imidazole (2.15 g, 0.017 mol, 98% purity) were added. The mixture was heated to between 158 and 167° C. for 5 h and then allowed to cool overnight. Water (20 mL) was added dropwise to the reaction mixture over 5 minutes while stirring. After stirring for an additional 1 h, the reaction mixture was filtered, and the solid collected was washed water (3×10 mL), xylenes (10 mL) and dried to a constant weight in a vacuum-oven at 80° C. to give the title compound as a light brown solid (3.4 g).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:9])[CH:8]=CC=CC=1.[CH3:10][O:11][CH:12]([O:20][CH3:21])[CH2:13][NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18].C(Br)C=C>O>[CH2:9]([N:14]([CH2:13][CH:12]([O:11][CH3:10])[O:20][CH3:21])[C:15](=[O:19])[O:16][CH2:17][CH3:18])[CH:3]=[CH2:8]
Reactant: CCOC(=O)NCC(OC)OC
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C=CCBr
Product: C=CCN(CC(OC)OC)C(=O)OCC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
20 g of sodium hydride (80% strength in paraffin oil) are initially introduced into 500 ml of toluene and 89 g (0.5 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate are added dropwise at 80° C. The mixture is stirred at 80° C. for one hour and 73 g (0.6 mol) of allyl bromide are then added dropwise in the course of three hours. The mixture is stirred at 80° C. overnight, the salts are dissolved with water and the organic phase is separated off. The aqueous phase is extracted with toluene, the organic phases are dried over potassium carbonate and concentrated and the residue is distilled.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C:21](O)=O)=[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.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC.O.[CH3:62][N:63]([CH3:66])[CH:64]=[O:65]>O1CCCC1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:20][CH2:21][C:64]([N:63]([CH3:66])[CH3:62])=[O:65])[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)[C@H](CC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (Compound SP444) (10.0 g, 23.5 mmol) was dissolved in dimethylformamide (70 ml), ((benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (12.5 g, 28.3 mmol) and dimethylamine (58 mmol) were added as a 2 mol/1 solution in tetrahydrofuran, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to afford tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(dimethylamino)-5-oxopentanoate (Compound SP447) (15.2 g) as a crude product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[NH:14][CH:8]([CH2:9][C:10](=[O:15])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2].CCN(CC)CC.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)(=[O:32])=[O:31])[CH:8]([CH2:9][C:10](=[O:15])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CC2CC(=O)CC(C1)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC2CC(=O)CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
7-Oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester (5.91 g, 27.9 mmol) was dissolved in methylene chloride (60 mL). Et3N (7.76 mL, 55.9 mmol) and 4-chlorobenzenesulfonyl chloride (7.08 g, 33.6 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with methylene chloride (50 mL) and washed with saturated NaHCO3 (50 mL). The aqueous phase was separated and extracted once with methylene chloride (50 mL). The combined organic phases were then dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified on a silica gel column (eluant hexane/EtOAc, 9/1 to 1/1) to give 9.52 g (88%) of 9-(4-chloro-benzenesulfonyl)-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester. Retention time (min)=2.100, method [1], MS (ESI) 408.1 (M+Na); 1H NMR (300 M Hz, CDCl3) δ 7.81 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 4.61-4.57 (m, 2H), 4.09 (q, J=7.1 Hz, 2H), 2.80 (dd, J=17.0, 7.1 Hz, 2H), 2.67-2.51 (m, 1H), 2.41 (d, J=16.4 Hz, 2H), 1.99-1.90 (m, 2H), 1.80 (dt, J=13.2, 4.4 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H).