Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:19]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(-c3cccnc3)c2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-pyridine-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-pyridin-3-yl-7-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 332(MH+).
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].O1CCOCC1.[H-].[Li+].Br[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=1>C(Cl)Cl.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>[CH3:28][O:27][C:25]1[CH:26]=[C:21]([S:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:8])[CH3:7])[CH:9]([CH3:11])[CH3:10])[CH:22]=[C:23]([O:29][CH3:30])[CH:24]=1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: COc1cc(Br)cc(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(OC)cc(S[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a solution of triisopropylsilanethiol (0.49 g, 2.6 mmol) in 1,4-dioxane (5 mL, 60 mmol) was added lithium hydride (23 mg, 2.9 mmol). After 10 minutes, 1-bromo-3,5-dimethoxy-benzene (500 mg, 2 mmol) and tetrakis(triphenylphosphine)palladium(0) (270 mg, 0.23 mmol) were added and the reaction mixture was heated to 60° C. for 16 h. The reaction mixture was diluted with DCM, filtered and concentrated. The resulting residue was dissolved in DCM and purified using silica gel chromatographie (40 g silica gel column) eluting with hexanes:DCM (3:1) to afford the title product.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:12])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][C:15]=1[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>>[Cl:12][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[C:15]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:16]=3)=[CH:3][N:4]=[C:5]2[C:10]=1[F:11]
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1
Reactant: Fc1c(Cl)ccn2c(Br)cnc12
Product: Fc1ccc(-c2cnc3c(F)c(Cl)ccn23)cc1-c1cccnc1
Yield: 79.7 %

Procedure:
3-Bromo-7-chloro-8-fluoroimidazo[1,2-α]pyridine (45 mg, 0.18 mmol) was coupled with 4-fluoro-3-(pyridin-3-yl)phenylboronic acid (49 mg, 0.19 mmol), as described in Example 1, to afford the title compound as a white amorphous solid (49 mg, 80%): δH (400 MHz, DMSO) 7.10 (1H, t, J 7.0), 7.54-7.61 (2H, m), 7.77-7.81 (1H, m), 7.92 (1H, dd, J 2.3, 7.4), 7.94 (1H, s), 8.09-8.12 (1H, m), 8.52 (1H, dd, J 1.0, 7.2), 8.65-8.66 (1H, m), 8.88 (1H, s); m/z (ES+) 342 (100%, [MH]+).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([OH:12])=O.[C:13]1([NH:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([NH:19][CH2:20][CH2:21][NH:22][C:10]([C:2]2[NH:1][C:5]3=[CH:6][N:7]=[CH:8][CH:9]=[C:4]3[CH:3]=2)=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCNc1ccccc1
Reactant: O=C(O)c1cc2ccncc2[nH]1
Product: O=C(NCCNc1ccccc1)c1cc2ccncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 15) and 2-phenylaminoethylamine to give the title compound as a pale yellow solid.
Reaction SMILES: C[Mg]I.COC(=O)/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1.[Cl-].[NH4+].C([O:27]CC)C>O1CCCC1>[CH3:7][CH:8]([OH:27])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1
Reactant: CCOCC
Reactant: COC(=O)/C=C/c1ccc(Cc2cccnc2)cc1
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cc2cccnc2)cc1

Procedure:
Under an atmosphere of nitrogen, 1.5 ml of a 3M solution of methylmagnesium iodide in diethyl ether were added to a solution of 830 mg of the aldehyde (prepared as described in Reference Example 1) in 20 ml of tetrahydrofuran at -70° C., the mixture was allowed to warm from -70° C. to room temperature over a period of one hour with stirring, poured into a saturated aqueous solution of amonium chloride, and extracted with diethyl ether. The extract was washed with water, and a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:1) as eluent to give 547 mg of the title compound having the following physical characteristics:
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)=O>>[F:24][C:20]1[CH:19]=[C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1cccc(F)c1
Agent: Cl
Product: N#Cc1ccnc(-n2nccc2-c2cccc(F)c2)c1
Yield: 98 %

Procedure:
The title compound was prepared in 98% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-3-(dimethylamino)-1-(3-fluorophenyl)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 6.53 (1H, d, J=1.6 Hz), 6.99-7.10 (3H, m), 7.29-7.35 (1H, m), 7.38-7.40 (1H, m), 7.78 (1H, d, J=2.0 Hz), 8.05 (1H, s), 8.38 (1H, d, J=4.8 Hz).
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[C:15]([C:48]([F:51])([F:50])[F:49])=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C@:24]([NH:40]C(=O)OC(C)(C)C)([CH3:39])[CH2:25][O:26][P:27]([O:34]C(C)(C)C)([O:29]C(C)(C)C)=[O:28])[CH:18]=[CH:17]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.Cl.O>>[P:27]([OH:34])([OH:29])([O:26][CH2:25][C@:24]([NH2:40])([C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([O:13][C@H:10]3[CH2:11][CH2:12][C@H:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:8][CH2:9]3)[C:15]=2[C:48]([F:49])([F:51])[F:50])[CH:20]=1)[CH3:39])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C4CCCCC4)CC3)ccc2c1
Agent: Cl
Solvent: CO
Solvent: O
Product: C[C@](N)(COP(=O)(O)O)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C4CCCCC4)CC3)ccc2c1
Temperature: 80 °C

Procedure:
tert-Butyl (R)-2-(6-(trans-4-cyclohexylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-1-(di-tert-butoxyphosphoryloxy)propan-2-ylcarbamate was then dissolved in methanol (2 mL, 0.06 mol) followed by 6 M of hydrogen chloride in water (1 mL, 0.007 mol). The reaction mixture was then heated at 80° C. for 3 hours. All solvents were removed, the crude product was then purified via reverse chromatography (4.3 g, 10-90% acetonitrile with 0.1% TFA/water with 0.1% TFA 7.2 mg, 17%). 1H NMR (MeOD) δ: 8.24 (d, J=8.8 Hz, 1H), 8.11 (d, J=9.3 Hz, 1H), 7.98 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.57 (d, J=9.3 Hz, 1H), 4.43-4.56 (m, 1H), 4.33 (d, J=8.3 Hz, 1H), 4.19 (d, J=7.0 Hz, 1H), 2.18 (d, J=10.5 Hz, 2H), 1.81-1.91 (m, 5H), 1.71-1.79 (m, 4H), 1.67 (d, J=11.5 Hz, 1H), 1.40-1.57 (m, 2H), 1.10-1.32 (m, 7H), 0.97-1.08 (m, 2H). MS (M+1): 530.0
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([CH3:8])[C:3]1=[NH:9].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[N:18]=[C:19]=[O:20]>O1CCCC1>[CH3:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([CH3:8])[C:3]1=[N:9][C:19]([NH:18][C:12]1[C:11]([CH3:10])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:17])=[O:20]
Reactant: Cc1cccc(C)c1N=C=O
Reactant: CN1CC(=O)N(C)C1=N
Solvent: C1CCOC1
Product: Cc1cccc(C)c1NC(=O)N=C1N(C)CC(=O)N1C

Procedure:
A mixture of 6.35 g (0.050 mole) of 1,3-dimethyl-2-iminoimidazolidin-4-one and 7.25 g (0.050 mole) of 2,6-dimethylphenylisocyanate in 75 ml. of dry tetrahydrofuran is stirred at room temperature for two hours followed by refluxing it for thirty minutes. The reaction mixture is evaporated in vacuo to give a solid, which is crystallized from tetrahydrofuran-ether. Two more recrystallizations from the same solvent mixture gives pure product, 1-(1,3-dimethyl-4-oxo-2-imidazolidinylidene)-3-(2,6-dimethylphenyl) urea; m.p. 115.5°-118.5°C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cccc(O)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc(C=O)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-3-hydroxybenzaldehyde (4.55 g, 29 mmol) in DMF (30 mL) was added K2CO3 (4.8 g, 34.9 mmol) followed by MeI (2.7 mL, 43.6 mmol), and the mixture was stirred at room temperature for 16 hours. Following concentration in vacuo, the residual was taken up in ethyl acetate, washed with H2O, brine, dried over Na2SO4, and concentrated. Purification by column chromatography on silica gel with ethyl acetate/hexanes 1/5 afforded 2-chloro-3-methoxybenzaldehyde 7a (4.68 g, 94%) as a colorless oil, which solidified upon standing. GCMS (EI) m/z 170, 172 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][C:16](Br)=[CH:15][C:3]=1[C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5].[Cu](C#N)[C:22]#[N:23]>CN(C)C(=O)C>[NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][C:16]([C:22]#[N:23])=[CH:15][C:3]=1[C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5]
Reactant: CCCCC(CC)COC(=O)c1cc(Br)cc(C)c1N
Reactant: N#C[Cu]C#N
Solvent: CC(=O)N(C)C
Product: CCCCC(CC)COC(=O)c1cc(C#N)cc(C)c1N
Yield: 86.1 %

Procedure:
The above-described method (Example 2) was repeated to react 2-ethylhexyl 2-amino-5-bromo-3-methylbenzoate (2.00 g, 5.84 mmol) with copper cyanide (0.53 g, 5.96 mmol) in N,N-dimethylacetamide at 160° C. for 8 hours. Following working up similar to Example 2 and additional washing with aqueous 5% ethylenediamine solution, 2-ethylhexyl 2-amino-5-cyano-3-methylbenzoate (1.45 g, 76.7% of theory, 89.1 area % LC) was obtained as a brown oil.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:15][CH3:16])[C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:8]([OH:10])=[O:9])C.[CH:17](NC)(C)C>>[CH:15]([N:4]([CH3:2])[C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:8]([OH:10])=[O:9])([CH3:16])[CH3:17]
Reactant: CNC(C)C
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Agent: Cl
Product: Cc1cc(C(=O)O)cc(N(C)C(C)C)n1

Procedure:
The title compound is prepared in analogy to 2-diethylamino-6-methyl-isonicotinic acid hydrochloride using isopropylmethylamine; LC-MS: tR=0.54 min, [M+H]+=209.09; 1H NMR δ 1.37 (d, J=6.3 Hz, 6H), 2.64 (s, 3H), 3.17 (s, 3H), 4.50-4.60 (m, 1H), 7.16 (s, 1H), 7.62 (s, 1H).
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1.[CH3:12]I>C(Cl)Cl>[Cl:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([CH2:10][O:11][CH3:12])[N:9]=1
Reactant: OCc1coc(CCl)n1
Reactant: CI
Agent: N#N
Solvent: ClCCl
Product: COCc1coc(CCl)n1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(chloromethyl)oxazol-4-yl)methanol (8.00 g, 54.22 mmol) in CH2Cl2 (32.0 mL) was treated with MeI (4.05 mL, 65.06 mmol) followed by Ag2O (18.85 g, 81.32 mmol) and the resulting mixture (protected from light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil: TLC: rf (6:4 hept-EA)=0.31. LC-MS-conditions 07: tR=0.54 min, [M+H]+=162.00.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].Br[CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[OH:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(O)c(C)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCO)c(C)c1
Temperature: 60 °C
Yield: 45.8 %

Procedure:
To a solution of methyl 4-hydroxy-3-methyl-benzoate (3.03 g, 18.2 mmol) in DMF (9 mL) was added 3-bromopropan-1-ol (3.80 g, 2.4 mL, 27.4 mmol) and cesium carbonate (17.8 g, 54.7 mmol) and the reaction mixture was heated at 60° C. for 16 hours. The reaction mixture was cooled to room temperature and then partitioned between water (250 mL) and ethyl acetate (2×100 ml). The organic layers were combined, washed with brine solution (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to yield a crude oil that was purified by silica gel column chromatography eluting with EtOAc/hexanes (10-100%) to give methyl 4-(3-hydroxypropoxy)-3-methyl-benzoate (1.87 g, 46%) as a white solid. ESI-MS m/z calc. 224.0. Found 225.0 (M+1)+; Retention time: 1.27 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 7.94-7.77 (m, 2H), 6.85 (d, J=8.5 Hz, 1H), 4.18 (t, J=5.9 Hz, 2H), 3.98-3.82 (m, 5H), 2.24 (s, 3H), 2.10 (p, J=5.9 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].CC1(C)COB([C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH3:35])[CH:34]=2)OC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([CH3:35])[CH:34]=1
Reactant: Cc1cncc(B2OCC(C)(C)CO2)c1
Reactant: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1Br
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)c1
Temperature: 70 °C
Yield: 35 %

Procedure:
To a mixture of 3-(3-bromo-4-fluorophenyl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (150 mg, 0.42 mmol) and 3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-5-methylpyridine in 1,4-dioxane (5 ml) was added a solution of caesium carbonate (340 mg, 1.04 mmol) in water (0.5 ml). The reaction was degassed with nitrogen and tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.04 mmol) was added and the mixture heated at 70° C. for 1 h. The solvent was evaporated in vacuo and the residue was partitioned between dichloromethane and water. The aqueous phase was re-extracted with dichloromethane and the combined organic layers dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified using a short silica gel column eluting with 2% diethyl ether in dichloromethane followed by 15% diethyl ether in dichloromethane to give a yellow solid. This was purified further by loading as a solution in methanol onto a cartridge of strong cation-exchange resin, eluting with methanol then with 2M ammonia in methanol. The basic fractions were concentrated in vacuo to give a dark cream solid. The solid was triturated with diethyl ether to give 3-[4-fluoro-3-(5-methylpyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a cream solid (55 mg, 35%): δH (360 MHz, d6-DMSO) 2.39 (3H, s), 7.51 (1H, d, J 7), 7.60 (1H, dd, J 11 and 9), 7.85 (1H, ddd, J 9, 5 and 2), 7.91-7.94 (1H, m), 8.00 (1H, dd, J 7 and 2), 8.33 (1H, s), 8.49 (2H, d, J 2), 8.68-8.71 (1H, m), 9.36 (1H, d, J 7); m/z (ES+) 373 (M++H).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:29])[C@@H:12]([NH2:28])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH3:9][C:2]([NH:10][C:11](=[O:29])[C@@H:12]([NH:28][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
To 80 ml of a methylene chloride solution containing 2.14 g of (2S)-N-(α,α-dimethylbenzyl)-2-amino-6-(benzyloxycarbonylamino)hexanamide (prepared as described in Preparation 9) and 0.51 g of pyridine were added dropwise, whilst ice-cooling, 30 ml of a methylene chloride solution containing 0.76 g benzoyl chloride, over a period of 10 minutes, with stirring. The mixed solution was stirred for a further 1.5 hours at room temperature, and then the solvent was distilled off. The residue was dissolved in ethyl acetate containing a small amount of water. A 10% w/v aqueous solution of citric acid was added, and then the solution was extracted with ethyl acetate. The extract was washed with a 5% w/v aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. The fraction eluted with a 1:1 by volume mixture of ethyl acetate and hexane gave 2.06 g of the title compound as an amorphous substance melting at 53°-58° C. (with decomposition)
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([C:32]1[CH:33]=[C:34]([NH:43][CH2:44][C:45]([OH:47])=O)[C:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.CCN(CC)CC>CN(C=O)C>[CH2:25]([C:32]1[CH:33]=[C:34]([NH:43][CH2:44][C:45]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[O:47])[C:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ncc(Cc2ccccc2)cc1NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc(Cc2ccccc2)cc1NCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
HATU (494 mg, 1.3 mmol) was added via spatula to a solution of N-[5-benzyl-2-(ethoxycarbonyl)pyridin-3-yl]glycine (328 mg, 1.04 mmol), morpholine (0.113 mL, 1.3 mmol) and Et3N (0.18 mL, 1.3 mmol) in DMF (6 mL). After stirring for 45 min at rt, the solvent was removed in vacuo and the resulting material was dissolved in CH2Cl2 and washed with water. The organic layer was dried and concentrated. Purification of the crude material by silica gel chromatography eluting with 0-5% MeOH/CH2Cl2 afforded the product: 1H NMR (CDCl3) δ 8.57 (1H, br), 7.94 (1H, s), 7.23 (3H, m), 7.15 (2H, m), 6.68 (1H, s), 4.46 (2H, q, J=7 Hz), 3.95 (2H, s), 3.90 (2H, d, J=4.2 Hz), 3.68 (6H, br), 3.43 (2H, br), 1.42 (3H, t, J=7 Hz); ES+ MS: 384 (M+H+, 70).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([C:9]([OH:11])=O)[CH:5]=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=4[CH3:8])=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: CCn1ncc(C(=O)O)c1C
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)c1C
Temperature: 79 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
A dry flask was charged with 1-Ethyl-5-methyl-1H-pyrazole-4-carboxylic acid (0.159 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 1-Ethyl-5-methyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.236 g, 0.61 mmol, 59%).
Reaction SMILES: C[N:2]1[CH:7]=[CH:6][C:5](C2C=CC(C)=CC=2)=[CH2+:4][CH:3]1[O-].C([S@](C1C=CC(C)=CC=1)=O)=C.[O:27]1[CH2:32][CH2:31]OCC1>>[CH:3]12[NH:2][CH:7]([CH2:5][CH2:4]1)[CH:6]=[CH:31][C:32]2=[O:27]
Reactant: Cc1ccc(C2=[CH2+]C([O-])N(C)C=C2)cc1
Reactant: C1COCCO1
Agent: C=C[S@@](=O)c1ccc(C)cc1
Product: O=C1C=CC2CCC1N2

Procedure:
A solution of 1-methyl-4-(p-tolyl)-3-pyridiniumolate 26 (1.86 g, 8.37 mmol) and (+)-(R)-p-tolyl vinyl sulphoxide (1.07 g, 6.45 mmol) in dioxane (50 mL) was allowed to reflux for 20 hours. The resulting reaction mixture was concentrated under reduced pressure, purified by silica gel flash chromatography, and recrystallized from EtOAc to give the compound 29 as a white solid: [α]25D −47° (c 0.8, CH2Cl2); Rf0.6 (EtOAc); mp 188° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:26])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23]O)[CH:20]=[CH:21][CH:22]=1.P(Br)(Br)[Br:28]>ClCCl>[Br:28][CH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:6]1[C:5]([O:25][CH3:26])=[N:4][C:3]2[C:7]1=[N:8][C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:10][C:2]=2[NH2:1]
Reactant: BrP(Br)Br
Reactant: COCCOc1nc(N)c2nc(OC)n(Cc3cccc(CO)c3)c2n1
Solvent: ClCCl
Product: COCCOc1nc(N)c2nc(OC)n(Cc3cccc(CBr)c3)c2n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of Compound 7 (65 mg, 0.18 mmol) in dichloromethane (2 mL) was cooled to 0° C. and phosphorus tribromide (17 μL, 48.9 mg, 0.18 mmol) was added by syringe. The reaction mixture was stirred at 0° C. and the progress of the reaction was monitored by TLC (silica gel, eluting 10% methanol in ethyl acetate). After 20 minutes, the reaction mixture was quenched with saturated sodium bicarbonate solution, washed with water, and the combined organic layers were dried over sodium sulfate and evaporated to dryness. The crude mixture containing Compound (11) was used in the next step without further purification. LCMS: m/z for C17H20BrN5O3++H observed 423 and 424.1 at 1.42 minutes of a 3.0 minute run, eluting 5-95% CH3CN in H2O (C18 column).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]([NH2:34])=[O:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][C:32]([NH2:34])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: NC(=O)Nc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: NC(=O)Nc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-(2-bromophenyl)urea. MS (ESI): mass calcd. for C17H14FN5O, 323.12; m/z found, 323.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.02 (s, 1H), 7.95 (m, 1H), 7.86 (d, J=8.9, 1H), 7.56 (s, 1H), 7.36-7.19 (m, 4H), 7.08 (m, 1H), 6.73 (s, 2H), 6.01 (s, 2H).