Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18](O)=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([NH:32][C:31]4[CH:33]=[CH:34][C:28]([C:27]([F:26])([F:35])[F:36])=[CH:29][CH:30]=4)=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: Nc1ccc(C(F)(F)F)cc1
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: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 74.2 %

Procedure:
In the same manner as in Example 278 and using 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoic acid (150 mg, 0.42 mmol), 4-(trifluoromethyl)aniline (191 mg, 1.2 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (230 mg, 0.6 mmol), N,N-diisopropylethylamine (160 mg, 1.3 mmol) and N,N-dimethylformamide (5 mL) as starting materials, the title compound (155 mg, 74%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH:59]1[CH2:64][CH2:63][CH:62]([C:65]2[C:66](=[O:75])[NH:67][C:68]3[C:73]([CH:74]=2)=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:61][CH2:60]1>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:23])[F:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:18])[N:59]4[CH2:60][CH2:61][CH:62]([C:65]5[C:66](=[O:75])[NH:67][C:68]6[C:73]([CH:74]=5)=[CH:72][CH:71]=[CH:70][CH:69]=6)[CH2:63][CH2:64]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
(S)-2-(1,4-Dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (44 mg, 0.088 mmol) was dissolved in N,N-dimethylformamide (1.5 mL). N,N-Diisopropylethylamine (70 μl, 0.402 mmol) was added to the mixture followed by TBTU (31.5 mg, 0.098 mmol). 3-(Piperidin-4-yl)quinolin-2(1H)-one hydrochloride (25.7 mg, 0.097 mmol) was added to the mixture. Reaction stirred at room temperature for 1.5 hours. Reaction was quenched with 50% acetonitrile-water. Mixture was purified by reverse phase prep HPLC (acetonitrile-water-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as light tan solid in 51% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.91 (s, 1H) 11.78 (s, 1H) 7.71 (s, 1H) 7.62 (d, J=7.93 Hz, 1H) 7.48 (s, 1H) 7.44 (t, J=7.63 Hz, 1H) 7.28 (d, J=8.24 Hz, 1H)7.15 (t, J=7.48 Hz, 1H) 5.58 (d, J=17.70 Hz, 1H) 5.40 (d, J=17.40 Hz, 1H) 4.55 (d, J=11.90 Hz, 1H) 4.29-4.46 (m, 1H) 4.07-4.23 (m, 2H) 3.91-4.05 (m, 1H) 3.11-3.24 (m, 2H) 2.95-3.09 (m, 2H) 2.82-2.95 (m, 1H) 2.64 (t, J=13.12 Hz, 1H) 2.43 (dd, J=16.48, 4.27 Hz, 1H) 1.89-1.96 (m, 1H) 1.78-1.88 (m, 1H) 1.47-1.64 (m, 1H) 1.30-1.46 (m, 1H). High resolution MS m/e (M+H)+=708.0445.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[Cl:1][CH:2]=[CH:3][CH2:4][C:5]12[O:19][CH:6]1[CH:7]=[CH:8][CH:9]=[CH:10]2
Reactant: ClC=CCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: ClC=CCC12C=CC=CC1O2
Reaction time: 72 h
Yield: 39.3 %

Procedure:
16.6 g of o-chloroallylbenzene was dissolved in 100 ml of chloroform and to the mixture was added dropwise, while maintaining the temperature at 0° - 5° C, 25 g of m-chloroperbenzoic acid dissolved in 600 ml of chloroform. The resulting mixture was allowed to stand at the same temperature for 72 hours. After the separated m-chlorobenzoic acid was filtered off, the filtrate was washed with 10% sodium hydroxide solution, then with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was distilled under reduced pressure to give 7.2 g (yield 38.8%) of o-chloroallylbenzene oxide having a boiling point of 93° C/3 mmHg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([O:37][CH3:38])[C:35]=1[F:36].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:33]=[C:34]([O:37][CH3:38])[C:35]([F:36])=[C:30]([F:29])[CH:31]=1
Reactant: COc1cc(B(O)O)cc(F)c1F
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc(F)c1F
Temperature: 100 °C
Yield: 57.6 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (200 mg, 0.3 mmol) was treated with (3,4-difluoro-5-methoxyphenyl)boronic acid (93 mg, 0.49 mmol), 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (29 mg, 0.03 mmol) and aqueous solution of sodium carbonate (2M, 492 μl, 0.98 mmol) in dioxane. The reaction mixture was submitted at vacuum-argon cycles and heated at 100° C. overnight. The solvent was cooled at room temperature and diluted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by reverse phase using SP1® Purification System to obtain 87 mg (53% yield) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:53])[CH:3]1[CH2:6][N:5]([C:7]([C@@H:9]2[CH2:13][C@H:12]([S:14][C:15]3[C@H:16]([CH3:39])[C@@H:17]4[C@@H:34]([C@H:35]([OH:37])[CH3:36])[C:33](=[O:38])[N:18]4[C:19]=3[C:20]([O:22]CC3C=CC([N+]([O-])=O)=CC=3)=[O:21])[CH2:11][N:10]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:8])[CH2:4]1.[H][H]>O1CCCC1.O.[Pd]>[CH3:53][N:2]([CH3:1])[CH:3]1[CH2:4][N:5]([C:7]([C@@H:9]2[CH2:13][C@H:12]([S:14][C:15]3[C@H:16]([CH3:39])[C@@H:17]4[C@@H:34]([C@H:35]([OH:37])[CH3:36])[C:33](=[O:38])[N:18]4[C:19]=3[C:20]([OH:22])=[O:21])[CH2:11][NH:10]2)=[O:8])[CH2:6]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC(N(C)C)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC(N(C)C)C4)C3)[C@H](C)[C@H]12

Procedure:
0.75 g of 4-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-(3-dimethylaminoazetidin-1-ylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in Example 129(1)] was dissolved in a mixture of 21 ml of tetrahydrofuran and 14 ml of water, and 0.75 g of a 10% w/w palladium-on-carbon catalyst was added to the resulting solution, after which the mixture was hydrogenated at room temperature for 1.5 hours in an atmosphere of hydrogen. At the end of this time, the catalyst was removed by filtration and the filtrate was washed with diethyl ether. The resulting aqueous solution was then concentrated by evaporation under reduced pressure, after which the residue was subjected to reverse phase column chromatography [Cosmosil 75C18 -prep, 25 g, manufactured by Nacalai Tesque). Of the fractions obtained by elution with 7% by volume aqueous acetonitrile, the fraction containing the title compound was concentrated by evaporation under reduced pressure and freeze-dried, to obtain 171 mg of the title compound as a powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[S:17])[NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[CH3:2].C[C:19](C)([O-:21])C.[Li+]>CN(C)C=O>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][N:5]1[CH2:2][C@@H:1]([CH2:19][OH:21])[O:3][C:4]1=[S:17]
Reactant: CCOC(=S)NCCOc1ccccc1OC
Reactant: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1ccccc1OCCN1C[C@@H](CO)OC1=S

Procedure:
Using N,N-dimethylformamide solution of ethyl-2-(2-methoxyphenoxy)ethylthiocarbamate 25.5 g (0.1 mol) [J. Chem. Soc., 1952, 2076; J. Chem. Soc., 1952, 2079; Tetrahedron Lett., 1969, 3631], lithium-t-butoxide 1.6 g (0.02 mol) and (S)-2-oxyranylmethoxy-tetrahydropyran 17.38 g (0.11 mol), the procedures as described in Example 1 were carried out to obtain the targeted product.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[C:11]1([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[C:11]1([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]3[CH:2]=[C:1]([C:3]4[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=4)[O:28][N:27]=3)=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(CSc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(CSc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridine-2,6-diamine (50 mg, 0.376 mmol) described in Manufacturing Example 13-1-3 and (4-phenylsulfanylmethyl-phenyl)acetohydroximoyl chloride (176 mg, 0.602 mmol) described in Manufacturing Example 206-1-6 was added triethylamine (131 μL, 0.94 mmol), which was stirred for 2 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1, then ethyl acetate) to obtain the title compound (98 mg, 67%).
Reaction SMILES: [H-].[Na+].O([C:10]([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])C1C=CC=CC=1.N[C@H](C(O)=O)C(C)C.[CH3:28][NH:29][CH2:30][C:31]1[N:32]=[C:33]([CH:36]([CH3:38])[CH3:37])[S:34][CH:35]=1>C1COCC1>[CH3:28][N:29]([C:10]([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH2:30][C:31]1[N:32]=[C:33]([CH:36]([CH3:38])[CH3:37])[S:34][CH:35]=1
Reactant: CNCc1csc(C(C)C)n1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Agent: CC(C)[C@H](N)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred slurry of anhydrous 95% NaH (500 mg, 20.8 mmol) at -10° C. in 25 mL of THF was added N-phenoxycarbonyl-L-Valine (4.93 g, 20.8 mmol) followed by a 10 mL THF rinse keeping the temperature <0° C. using an ice-water bath. Following the addition of the N-protected Valine, N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (3.54 g, 20.8 mmol) was added at <0° C. The reaction was allowed to warm to ambient temperature. After 3 hours, 50 mL of THF was added followed by 25 mg (1 mmol) of NaH. After 16 hours at room temperature, the reaction was complete. The reaction was worked up by the procedures described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6]1.[H-].[Na+].[CH3:23]I.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]([S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:12])=[O:13])([CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6]1)[CH3:23]
Reactant: COC(=O)C(C1CCC(=O)C1)S(=O)(=O)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C1CCC(=O)C1)S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 31 %

Procedure:
To a stirred solution of 2.4 g (8.1 mmol) of benzenesulfonyl-(3-oxo-cyclopentyl)-acetic acid methyl ester in 15 mL of DMF at 0° C., 389 mg (8.9 mmol, 1.1 eq) of NaH (60%) were added. The reaction mixture was stirred at this temperature for one hour, and 1.72 g (12.1 mmol, 1.5 eq) of methyliodide were added. After 2 hours at RT, the reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. The resulting two diastereomers were separated by column chromatography on silica gel with heptane/EtOAc (from 2:1 to 2:1) yielded 0.78 g (31%) of (RS,SR)-2-benzenesulfonyl-2-(3-oxo-cyclopentyl)-propionic acid methyl ester as a white solid, MS: 311 (MH+) and 0.53 g (21%) of (RR,SS)-2-benzenesulfonyl-2-(3-oxo-cyclopentyl)-propionic acid methyl ester as a white solid, MS: 311 (MH+).
Reaction SMILES: [O:1]1[CH2:3][CH2:2]1.[Mg].Cl[CH2:6][C:7]1[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=1.S(=O)(=O)(O)O>C(OCC)C>[F:14][C:13]([F:15])([F:16])[C:9]1[CH:8]=[C:7]([CH2:6][CH2:3][CH2:2][OH:1])[CH:12]=[CH:11][CH:10]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: C1CO1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: OCCCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A solution of 57 g of oxirane in 120 ml of diethyl ether is added dropwise, at 0° to 10° C., to a Grignard solution prepared from 14.8 g of magnesium and 100 g of 3-(chloromethyl)benzotrifluoride in 450 ml of diethyl ether. The mixture is subsequently stirred at room temperature for 1 hour and 300 ml of 10% strength sulfuric acid are then added, while cooling with ice. The organic phase is collected and extracted twice more with diethyl ether and the combined organic phases are dried over magnesium sulfate and distilled. 76.7 g of 3-(3-trifluoromethylphenyl)propan-1-ol of b.p. 85° to 95° C. under 0.02 mm Hg are obtained.
Reaction SMILES: Br[C:2]1[C:3]([C:12]#[N:13])=[N:4][CH:5]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[N:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:2]3[C:3]([C:12]#[N:13])=[N:4][CH:5]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[N:7]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: N#Cc1ncc(NCCO)nc1Br
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ncc(NCCO)nc1N1CCN(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 82c, 3-bromo-5-(2-hydroxy-ethyl-amino)-pyrazine-2-carbonitrile was treated with 1-(4-fluorophenyl)piperazine in the presence of potassium carbonate in N,N-dimethylformamide between room temperature and 80° C. to yield 4-(4-fluoro-phenyl)-6′-(2-hydroxy-ethylamino)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-carbonitrile as light yellow solid; m.p. 149-151° C.; MS: 343 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12]C([O-])=O>N1CCCCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:12][C:11]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cn1
Reactant: CCOC(=O)CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)C=Cc1ccc(OC)nc1
Yield: 79.2 %

Procedure:
A mixture of 6-methoxypyridine-3-carboxaldehyde (2.34 g), monoethyl malonate (4.51 g), pyridine (12 ml) and piperidine (6 drops) was heated under reflux for 5 hours and was evaporated to an oil. This oil was partitioned between ether and dilute aqueous ammonia. The separated ether layer was washed with water and evaporated to an oil which crystallised on standing to give ethyl 3-(6-methoxy-3-pyridyl)acrylate (2.8 g, 79%), m.p. 49°-52°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([Cl:14])[N:8]=1.Cl.C(N(CC)CC)C.[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33])([O-:28])=[O:27]>C1COCC1>[Cl:14][C:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=3)[CH:17]=[CH:16][CH:15]=2)[C:12]([Cl:13])=[CH:11][N:10]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1cccc(CNc2nc(Cl)ncc2Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(CNc2nc(Cl)ncc2Cl)c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a mixture of N-(3-aminobenzyl)-2,5-dichloropyrimidin-4-amine.hydrogen chloride (0.10 g, 0.29 mmol) (prepared according to Example 3, step B) and triethylamine (0.16 mL, 1.2 mmol) in THF (3 mL) was added slowly 3-nitrobenzoyl chloride (54 mg, 0.29 mmol). The resulting mixture was stirred at rt for 2 hours and concentrated under vacuum. The residue was partitioned in EtOAc and water. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give the desired product as a yellow solid (90 mg, 70%). LCMS for C18H14Cl2N5O3 (M+H)+: m/z=418.0, 420.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:27]12[CH2:35][C:31]([CH2:36][NH2:37])([CH2:32][CH2:33][CH2:34]1)[CH2:30][CH2:29][CH2:28]2>O1CCCC1.CO>[N:27]12[CH2:35][C:31]([CH2:36][NH:37][C:7](=[O:9])[C:6]3[CH:10]=[C:2]([Cl:1])[C:3]([NH:13][CH3:14])=[CH:4][C:5]=3[O:11][CH3:12])([CH2:32][CH2:33][CH2:34]1)[CH2:30][CH2:29][CH2:28]2
Reactant: CNc1cc(OC)c(C(=O)O)cc1Cl
Reactant: NCC12CCCN(CCC1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(OC)c(C(=O)NCC23CCCN(CCC2)C3)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A solution of 5-chloro-2-methoxy-4-(methylamino)benzoic acid (1.08 g, 5 mmol) in anhydrous tetrahydrofuran (7 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (0.90 g, 5.5 mmol), stirred one hour, degassed under a stream of nitrogen for 10 minutes, and cooled (0° C.). A solution of 1-azabicyclo[3.3.1]nonane-5-methanamine (0.82 g, 5.3 mmol) in tetrahydrofuran (3 mL) was added dropwise, and stirring was continued at room temperature for 18 hours. The suspension was diluted with enough methanol to dissolve the solid, then the solution was filtered through a short column of alumina (eluted with 20% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, triturated from cold ether, and recrystallized from acetonitrile to afford 1.29 g (73%) of colorless crystals; mp 188°-190° C. (second phase), first phase melting point 175° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.Cl[C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccc(F)cc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of 2,4-difluoroaniline (10 g, 77 mmol) and triethylamine (12.95 mL, 93.00 mmol) in THF (50 mL) was added ethyl 2-chloro-2-oxoacetate (9.05 mL, 81.0 mmol) drop wise at 0° C. A white solid precipitated instantly. The reaction mixture was stirred at rt for 1 h. The solvent was evaporated, and Et2O was added. The solution was washed with 1N HCl (20 mL), saturated NaHCO3 and then brine, then the organic layer dried over MgSO4, filtered and concentrated to give Intermediate 11A (15.8 g, 68.9 mmol, 89.0% yield) as a white crystalline solid. HPLC/MS (Method L) RT=1.58 min, [M+H]+ 230.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:41]([C:43]1[N:44]=[C:45]([C:56]([O-])=[O:57])[N:46]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:47]=1)#[N:42].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:56]([C:45]3[N:46]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:47]=[C:43]([C:41]#[N:42])[N:44]=3)=[O:57])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2ncccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2ncccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 53.3 %

Procedure:
A solution of 80.0 mg (0.395 mmol) of 2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-ylamine (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 277 mg (0.593 mmol) of PyBroP, 133 mg (0.435 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)), and 207 μL (1.19 mmol) of DIEA. The mixture was stirred at RT for 17 h, diluted with CH2Cl2 (20 mL) and washed with water (1×10 mL). The aqueous layer was extracted with CH2Cl2 (1×10 mL), and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 10-g Isolute SPE column with 25% EtOAc-hexane afforded 95 mg (53%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 9.92 (br s, 1H), 8.72 (dd, 1H, J=8.0, 1.6 Hz), 8.37 (dd, 1H, J=4.4, 1.6 Hz), 7.77 (s, 1H), 7.23-7.18 (m, 1H), 6.00-5.94 (m, 1H), 5.93 (s, 2H), 3.70-3.63 (m, 2H), 2.51-2.43 (m, 2H), 2.18-2.11 (m, 2H), 1.61 (t, 2H, J=6.4 Hz), 1.12 (s, 6H), 1.00-0.94 (m, 2H), 0.00 (s, 9H).