Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:17]2[NH:11][C:12](=[O:13])[NH:14][C:15]2=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C1CNC(=O)N1
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc(C=C2NC(=O)NC2=O)cc1

Procedure:
36.7 g (0.28 mol) of 4-cyanobenzaldehyde, 10 g (0.1 mol) of hydantoin, 21.6 g (0.263 mol) of sodium acetate and 28.6 ml (0.3 mol) of acetic anhydride are heated under reflux in 85 ml of acetic acid for 4 hours. After cooling, the mixture is poured onto ice and extracted with methylene chloride. The methylene chloride phase is concentrated, and the residue is stirred with methanol and filtered off with suction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:15])=[N+:12]([O-])[CH:13]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:15][Cl:18])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc(F)cc2)c[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(-c2ccc(CCl)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-fluorophenyl)-2-methylpyridine-N-oxide (2.9 g, 14.5 mmol) in CH2Cl2 (15 mL) is added a 1.5 mL portion of a CH2Cl2 (15 mL) solution of POCl3 (1.72 g, 1.7 mmol). Subsequently, the remainder of this POCl3 solution and a solution of triethylamine (1.76 g, 17.4 mmol) in CH2Cl2 (15 mL) are added simultaneously, so as to maintain reflux. After addition is complete the resulting solution is stirred at ambient temperature for 2 hours. The reaction mixture is then neutralized by addition of saturated NaHCO3 (50 mL). The organic phase is separated, dried over MgSO4 and concentrated in vacuo. Chromatography (silica gel, 1:1 EtOAc/hexanes) affords 5-(4-fluorophenyl)-2-(chloromethyl)pyridine as a yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:8][C:9](OCC)=O)(=[O:7])[CH:4]([CH3:6])[CH3:5].Br[CH2:15][C:16](C)=[CH:17][CH2:18][CH2:19][C:20]([CH3:27])=[CH:21][CH2:22][O:23]C(=O)C>CCOCC>[CH3:27][C:20]([CH2:19][CH2:18][CH:17]=[C:16]([CH3:15])[CH2:9][CH2:8][C:3](=[O:7])[CH:4]([CH3:5])[CH3:6])=[CH:21][CH2:22][OH:23]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: CC(=O)OCC=C(C)CCC=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=CCO)CCC=C(C)CCC(=O)C(C)C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a suspension of sodium hydride (1.9 g) in ether (40 ml) while cooling with ice, ethyl isobutyroylacetate (5.2 g) is added, and 1-bromo-8-acetoxy-2,6-dimethyl-2,6-octadiene (8 g) is dropwise added thereto. The reaction is carried out with reflux for 8 hours. The ether layer is separated from the reaction mixture, washed with water, dried and evaporated. The oily product (9.9 g) is added to a solution of potassium hydroxide (6.3 g) ethanol (120 g), and refluxing is continued for about 1 hour. The resultant mixture is added to the ice water, made acidic with 10% sulfuric acid and extracted with ether. The ether extract is washed with saturated aqueous solution of sodium chloride, aqueous solution of sodium hydrogen carbonate and water in order, and then the ether is evaporated therefrom. The residue (7.2 g) is dissolved in benzene and purified by chromatography on silica gel to give 3,7,11,-trimethyl-2,6-dodecadien-10-on-1-ol (6.2 g). NMR (carbon tetrachloride): δ 1.05 (d), 1.59 (s), 2.0 (s), 21.-2.7 (m), 3.52 (s), 3.95 (d), 4.8-5.4 (m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:19]=[CH:18][C:17]=2[F:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:19]=[CH:18][C:17]=2[F:29])[S:31]([CH3:30])(=[O:33])=[O:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2cc(-c3ccnc(Cl)n3)ccc2F)CC1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cc(-c3ccnc(Cl)n3)ccc2F)S(C)(=O)=O)CC1

Procedure:
Intermediate 90 was coupled with methanesulfonyl chloride following procedure D LC-MS showed the product was >95% pure and had the expected M+H+ of 499.
Reaction SMILES: [C:1]([O:7][CH:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[BH4-].[Na+]>C(O)C>[C:1]([O:7][CH:8]1[CH2:9][CH:10]([OH:12])[CH2:11]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OC1CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=O)OC1CC(O)C1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-oxocyclobutyl pivalate (15.1 g, 88.7 mmol) in ethanol (100 ml) at 0° C. was added sodium borohydride (4.69 ml, 133 mmol) in several portions. The reaction was stirred for 30 min, slowly quenched with 10% aqueous HCl and concentrated to remove ethanol. The solution was taken up with more 10% HCl, extracted with DCM (3×), washed with brine, dried over MgSO4 and concentrated to give the title compound as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:20]=1[CH:21]=[CH:22][C:23](O)=O>>[CH2:13]([N:4]1[C:3](=[O:16])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][C:28]([O:32][CH3:33])=[C:29]([O:30][CH3:31])[C:19]=3[O:18][CH3:17])=[N:8][C:7]=2[N:6]([CH2:9][CH2:10][CH3:11])[C:5]1=[O:12])[CH2:14][CH3:15]
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1OC
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3OC)nc2n(CCC)c1=O
Yield: 48.5 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.00 g (8.85 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.32 g (9.73 mmol) of 2,3,4-trimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from 2-propanol/water to give 1.84 g (yield 49%) of Compound 21 as pale yellow needles.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CN.C1C[O:15][CH2:14]C1>C(O)C>[Br:1][C:2]1[C:3]([O:15][CH3:14])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: CN
Solvent: CCO
Product: COc1nc(Cl)ncc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a cooled (−78° C.) solution of 5-bromo-2,4-dichloropyrimidine (1.7 g, 7.3 mmol) in THF (30 mL) was added dropwise a 25 wt % solution of methylamine in ethanol (1.7 mL). The reaction was allowed to warm to 0° C. and stirred for 1 h. The reaction was then concentrated and re-dissolved in EtOAc. The solution was washed with brine, dried over Na2SO4, filtered and concentrated to give 5-bromo-2-chloro-4-methoxypyrimidine (1.25 g, 76%). 1H-NMR (CDCl3): δ 8.43 (s, 1H), 4.10 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:17])=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[C:18](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:19]>O1CCOCC1>[F:17][C:3]1[C:2]([N:1]=[C:18]=[S:19])=[C:15]([F:16])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)C(=O)NCc1ccc(F)c(N)c1F
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NCc1ccc(F)c(N=C=S)c1F

Procedure:
A mixture of N-(3-amino-2,4-difluoro-benzyl)-2,2-dimethyl-propionamide (570 mg, 2.35 mmol), 1,1′-thiocarbonyldi-2(1H)-pyridone (550 mg, 2.35 mmol) and dioxane (20 mL) is stirred at reflux overnight. The reaction mixture is concentrated, diluted with DCM, filtered through a pad of silica gel and the filtrate is concentrated to give the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]3[N:25]=[CH:26][C:27]4[C:32]5[CH:33]=[CH:34][N:35]=[C:36]([F:37])[C:31]=5[N:30]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:28]=4[N:29]=3)=[N:21][CH:22]=2)[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:38]1([N:30]2[C:28]3[N:29]=[C:24]([NH:23][C:20]4[N:21]=[CH:22][C:17]([N:14]5[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][OH:8])[CH2:16][CH2:15]5)=[CH:18][CH:19]=4)[N:25]=[CH:26][C:27]=3[C:32]3[CH:33]=[CH:34][N:35]=[C:36]([F:37])[C:31]2=3)[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.1 %

Procedure:
Compound 294 (78 mg, 132 μmol) was dissolved in dry THF (3 mL). Tetrabutylammonium fluoride, 1.0M in THF (1.00 mL, 1.00 mmol) was added and the reaction stirred at room temperature for 4 hours. The solvent was removed in vacuo and silica gel chromatography (gradient elution hexanes+2.5%/0-100% ethyl acetate+2.5% TEA) afforded compound 291 as a beige solid (44 mg, 70%). 1H NMR (500 MHz, DMSO-d6) δ 11.60-11.85 (m, 2 H) 9.49 (s, 2 H) 8.19-8.24 (m, 2 H) 8.13-8.19 (m, 2 H) 8.05-8.10 (m, 2 H) 7.96-8.04 (m, 2 H) 7.61-7.71 (m, 2 H) 5.48 (s, 1 H) 3.64 (d, J=11.98 Hz, 2 H) 3.44 (t, J=6.48 Hz, 2 H) 2.71-2.90 (m, 2 H) 2.20 (br. s., 2 H) 2.09 (br. s., 2 H) 2.00 (br. s., 2 H) 1.66-1.82 (m, 4 H) 1.52-1.66 (m, 1 H) 1.37 (d, J=6.60 Hz, 2 H) 1.28 (none, 2 H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Br[CH2:31][CH2:32][OH:33]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][CH2:32][OH:33])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: OCCBr
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCO)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 100 °C

Procedure:
5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) was dissolved in anhydrous DMF (1 mL). TEA (50 uL, 0.36 mmol, 3 equiv.) was added followed by 2-bromo-ethanol (0.018 mL, 0.24 mmol, 2 equiv.) dissolved in anhydrous DMF (0.7 mL). The reaction vessel was sealed and heated in a microwave at 100° C. for 20 min. After cooling to room temperature, the reaction was concentrated and the crude product was purified using preparative RP-HPLC to give 2-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)ethanol as a white solid: ESMS m/z 460.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:18])=[N:5][C:6](Cl)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH3:16])#[N:2].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1>CO>[Cl:18][C:4]1[C:3]([C:1]#[N:2])=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[CH3:16])[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][S:22][CH2:21][CH2:20]2)[N:5]=1
Reactant: C1CSCCN1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)nc(Cl)c1C#N
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc(N2CCSCC2)nc(Cl)c1C#N
Reaction time: 18 h
Yield: 88.4 %

Procedure:
Crude 3-cyano-2,6-dichloro-4-(4-fluoro-2-methylphenyl)pyridine, (32.44 g, 115.4 mmol) and 300 mL of methanol were added to a 500-mL, 3-necked flask (equipped with a 25-mL pressure-equilibrating addition funnel/dry N2 adapter, septum with teflon-coated thermocouple, and teflon paddle stirrer/glass shaft). Thiomorpholine (23.0 mL, 25.0 g, 242 mmol, 2.10 equiv) was added dropwise over a period of 22 minutes via the addition funnel, and the resulting mixture was stirred at 20–25° C. for 18 hours. The precipitate was filtered, washed with 30 mL of methanol, and dried to afford 35.47 g (88.4%) of 2-chloro-3-cyano-4-(4-fluoro-2-methylphenyl)-6-(thiomorpholino)pyridine as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:11]([CH2:16][CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12](=[O:15])[O:13][CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][C:27](=[CH2:31])[CH2:28][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([N:11]([CH2:16][CH2:17][C:18]([OH:25])([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:28][C:27]([CH3:31])=[CH2:26])[C:12](=[O:15])[O:13][CH3:14])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: C=C(C)C[Mg]Cl
Reactant: COC(=O)N(CCC(=O)c1ccccc1)C1(c2ccc(Br)cc2)CC1
Solvent: C1CCOC1
Product: C=C(C)CC(O)(CCN(C(=O)OC)C1(c2ccc(Br)cc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
A solution of methyl 1-(4-bromophenyl)cyclopropyl(3-oxo-3-phenylpropyl)carbamate (127 mg, 0.316 mmol) in dry THF (10 mL) was cooled to −78° C. A solution of 0.5M 2-methylallylmagnesium chloride in THF (1.9 mL, 3 equiv) was added. After 10min, the reaction mixture was warmed to rt slowly and stirred for 1 h. LC-MS found the reaction was complete. The mixture was quenched with satd aq NH4Cl (3 mL), diluted with ether (40 mL), washed with 1% aq HCl (8 mL), satd aq NaHCO3 (7 mL), and brine (5 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 12-g silica gel column, eluted with a 0˜30% EtOAc in hexanes gradient, to afford methyl 1-(4-bromophenyl)cyclopropyl(3-hydroxy-5-methyl-3-phenylhex-5-enyl)carbamate (58.8 mg, 41%).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:36]=[CH:35][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH:24]=2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:10]1([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([C:20](=[O:21])[NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH:24]=4)[CH:35]=[CH:36][C:16]=3[CH3:15])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Reactant: Cc1ccc(C(=O)Nc2cccc(-c3ccccn3)c2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(-c3ccccn3)c2)cc1-c1ccc(C(=O)NCC2CC2)cn1
Yield: 60.1 %

Procedure:
6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (18.5 mg, 0.073 mmol) and 4-methyl-N-(3-pyridin-2-yl-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 6) (30 mg, 0.072 mmol), aqueous sodium carbonate (2N, 0.5 ml) and tetrakis(triphenylphosphine)palladium (4 mg) were heated at 90° C. in DMF (1 ml) for 4 hours. The reaction was absorbed onto silica, applied to a bond-elut (5 g, silica) and eluted with an ethylacetate/cyclohexane (0 to 100%) and then acetone. The solvent was evaporated from the product fractions under vacuum and the residue triturated with ether to give N-cyclopropylmethyl-6-[2-methyl-5-(3-pyridin-2-yl-phenylcarbamoyl)-phenyl]-nicotinamide as a white solid (20 mg). LCMS: retention time 3.18 min, MH+ 463. NMR: δH [2H6]-DMSO 10.43,(1H, s), 9.14,(1H, s), 8.86,(1H, t), 8.69,(1H, s), 8.53,(1H, s), 8.34,(1H, d), 8.11,(1H, s), 8.01,(1H, d), 7.95–7.89,(3H, m), 7.81–7.78,(2H, m), 7.53–7.46, (2H, m), 7.38,(1H, t), 3.21,(2H, t), 2.44,(3H, s), 1.07,(1H, m), 0.47,(2H, m), 0.27,(2H, m).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:35]3[CH:38]=[CH:39][C:32]([O:31][C:30]([F:29])([F:40])[F:41])=[CH:33][CH:34]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Product: FC(F)(F)Oc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-trifluoromethoxy-benz aldehyde. MS (ESI) m/z 551.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:29][N:30](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]#[N:30])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2C(C)(C)C1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ccc(C#N)cc2C(C)(C)C1
Temperature: 100 °C
Yield: 85 %

Procedure:
Tetrakis (triphenylphosphine)palladium (0) (4.10 g, 0.0035 mol) was added to a suspension of N-tert-butyloxycarbonyl-4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline (36.37 g, 0.089 mol) and zinc cyanide (10.44 g, 0.089 mol) in anhydrous dimethyl formamide (280 ml) under argon. The resultant was heated at 100° C. for 4 hours, cooled and poured into water (800 ml). The mixture was filtered through kieselguhr and the filter cake washed with ethyl acetate. The bilayered filtrate was separated and the aqueous layer extracted into ethyl acetate (4×500 ml). Combined organics were washed with water (3×250 ml), brine (250 ml), dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel using 0-15 % ethyl acetate in hexane gradient elution to afford the title compound as a colourless oil (21.75 g, 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[NH:13][C:12]3=[O:19])=[CH:6][CH:5]=1)([O-])=O>CC(O)=O.O.[Fe]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[NH:13][C:12]3=[O:19])=[CH:6][CH:5]=1
Reactant: O=C1NC(=O)c2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ccc3c(c2)C(=O)NC3=O)cc1
Reaction time: 72 h
Yield: 74.6 %

Procedure:
A solution of 5-(4-nitrophenoxy)isoindoline-1,3-dione (0.6 g, 2.11 mmol) in conc. AcOH (12 mL) and water (0.1 mL) was stirred under stream of argon while iron powder (0.59 g, 55.9 mmol) was added slowly. This mixture stirred at room temp. for 72 h, then was diluted with water (25 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 5-(4-aminophenoxy)isoindoline-1,3-dione as a brownish solid (0.4 g, 75%): TLC (50% EtOAc/50% hexane) Rf 0.27; 1H NMR (DMSO-d6) δ5.14 (br s, 2H), 6.62 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 7.03 (d, J=2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J=8.4 Hz, 1H), 11.02 (s, 1H); HPLC ES-MS m/z 255 ((M+H)+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.F[C:25]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:33][C:32]1[C:25]([N:11]2[C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=3[C:9]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)=[N:10]2)=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]
Reactant: COc1nccc2[nH]nc(-c3ccc(N4CCOCC4)cc3)c12
Reactant: N#Cc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2-c1c(F)cccc1C#N
Yield: 77.4 %

Procedure:
A solution of 4-methoxy-3-(4-(morpholin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (355 mg), 2,3-difluorobenzonitrile (180 mg) and potassium carbonate in DMF (5 mL) was stirred at 100° C. for 2.5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid was washed with petroleum ether to give the title compound (380 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O1CCOCC1>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:6][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
To a solution of leucine methyl ester hydrochloride (5.0 g, 27.5 mmol) in 1,4-dioxane (50 mL) was added sodium carbonate (30.3 mL, 2M in water) followed by benzyl chloroformate (4.69 g, 27.5 mmol). The mixture stirred at room temperature for 24 hours when partitioned between ethyl acetate and water. The organic layer was collected, dried (MgSO4), filtered and concentrated to give the title compound as a colorless oil (7.67 g, 100%). 1HNMR (400 MHz, CDCl,) δ7.39 (m, SH), 5.38 (d, 2H), 5.12 (s, 2H), 4.42 (n, 1H), 3.75 (s, 3H), 1.73-1.50 (m, 3H), 0.94 (m, 6H).
Reaction SMILES: Cl.[C@@H:2]12[CH:7]([CH2:8][NH:9][C:10]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:18][CH:17]=4)=[C:14]([NH2:29])[N:13]=[CH:12][N:11]=3)[C@@H:6]1[CH2:5][NH:4][CH2:3]2.N1C=CC=CC=1.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38].C(Cl)Cl>>[NH2:29][C:14]1[N:13]=[CH:12][N:11]=[C:10]([NH:9][CH2:8][CH:7]2[C@@H:6]3[C@H:2]2[CH2:3][N:4]([C:36](=[O:39])[CH:37]=[CH2:38])[CH2:5]3)[C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:20][CH:21]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1ncnc(NCC2[C@H]3CNC[C@@H]23)c1-c1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)N1C[C@@H]2C(CNc3ncnc(N)c3-c3ccc(Oc4ccccc4)cc3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.8 %

Procedure:
To a round bottom flask containing N-[(1S,5R)-1-(3-Aza-bicyclo[3.1.0]hex-6-yl)methyl]-5-(4-phenoxy-phenyl)-pyrimidine-4,6-diamine hydrochloride (259.68 mg; 0.63 mmol; 1.00 eq.) in pyridine (1.00 ml; 12.36 mmol; 19.52 eq.) was added acryloyl chloride (0.05 ml; 0.63 mmol; 1.00 eq.) in DCM (3.00 ml; 46.80 mmol; 73.88 eq.) over 1 h at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. It was concentrated and the crude product was subjected to preparative HPLC. Fractions containing the desired product were combined and lyophilized overnight to afford 1-((1R,5S)-6-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one as a white solid (2.1 mg, 0.6%). HPLC purity: 99%. MS: m/z=428[M+H]+. 1H NMR (CD3OD) δ 8.24 (s, 1H), 7.21-7.46 (m, 9H), 6.53 (m, 1H), 6.22 (m, 1H), 5.74 (m, 1H), 3.77 (m, 2H), 3.69 (m, 1H), 3.41 (m, 2H), 1.70 (m, 2H), 0.93 (m, 2H).