Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:33][C:32]1[CH:31]=[C:30]([CH3:34])[NH:29][C:28](=[O:35])[C:27]=1[CH2:26][NH:25][C:24]([C:4]1[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][CH2:14]2)[CH:7]=[C:2]([C:41]2[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=2)[CH:3]=1)=[O:36]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(C)c3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Temperature: 100 °C

Procedure:
To a stirred solution of tert-butyl 4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)(methyl)amino)piperidin-1-carboxylate (1 equiv.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with, argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The reaction was heated at 100° C. for 5 h. After cooling, the reaction mixture was diluted with water, and the product was extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure to afford crude product which was purified by column chromatography over silica gel to afford tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methyl-5-(1-methyl-1H-pyrazol-4-yl)phenyl)(methyl)amino)piperidine-1-carboxylate. A stirred solution of this compound (1 mmol) in DCM (5 mL) was cooled to 0° C. and TFA (2 mL) was added to it. The reaction was stirred at room temperature for 1 h. On completion, the solution was concentrated to dryness. The residue was purified by solvent washings to afford the title compound (0.07 g, 87%). LCMS: 463.30 (M+1)+; HPLC: 98.02% (Ω254 nm) (Rt; 4.145; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.47 (bs, 1H), 8.12 (s, 2H), 8.05 (s, 1H), 7.83 (s, 1H), 7.32 (s, 1H), 7.14 (s, 1H), 5.86 (s, 1H), 4.28 (m, 2H), 3.84 (s, 3H), 3.24-3.27 (m, 2H), 3.11 (bs, 1H), 2.87-2.89 (m, 2H), 2.59 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H), 2.10 (s, 3H), 1.77-1.80 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[O:15]1[C:24]2[CH:23]=[C:22]([CH:25]=O)[N:21]=[CH:20][C:19]=2[O:18][CH2:17][CH2:16]1.[BH4-].[Na+].O>CO.ClCCl>[O:15]1[C:24]2[CH:23]=[C:22]([CH2:25][NH:1][CH2:2][CH:3]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]3)[N:21]=[CH:20][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNCc2cc3c(cn2)OCCO3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a solution of 0.28 g of tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate in a mixture of 7 mL of methanol and 20 mL of dichloromethane, 0.23 g of 2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde and 0.50 g of molecular sieves 3A were added, the mixture was stirred at room temperature for 3 hours, and then, the reaction mixture was charged with 79 mg of sodium borohydride and stirred at room temperature for 5 hours 30 minutes. Thereto was added water under cooling with ice, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.48 g of tert-butyl 3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)pyrrolidine-1-carboxylate as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[C@H:25]1([NH2:32])[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1.C(N(CC)CC)C>CS(C)=O>[NH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:32][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]4[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:26][CH2:27]1
Reactant: C[C@@H]1CC(CNc2cccc(-c3cc(F)ncc3Cl)n2)C[C@H](C)O1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CC(CNc2cccc(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)n2)C[C@H](C)O1
Temperature: 110 °C

Procedure:
The mixture of 5′-chloro-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2′-fluoro-2,4′-bipyridin-6-amine L (30 mg, 0.08 mmol), trans-1,4-cyclohexanediamine (49 mg, 0.43 mmol) and triethylamine (26 mg, 0.25 mmol) in 1.5 ml DMSO was heated in a reaction vessel at 110° C. in an oil bath for 16 h. Formation of desired product was confirmed by LC/MS. The reaction mixture solution was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. Crude compound was purified by HPLC to give desired product as TFA salt. LCMS (m/z): 444.2/446.2 (MH+), retention time=0.54 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>CCOCC>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1COc1cccnc1N
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccccc1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (1.19 g, 0.0056 mol), 4-chlorophenyl isothiocyanate (1.15 g, 0.0068 mol) and toluene (10 ml) was refluxed for 2.5 hours, then cooled and treated with ether to induce crystallisation of the product. Yield 1.63 g (77%), m.p. 181°-183 ° C.
Reaction SMILES: C1([C:7](=[N:14]CCCO)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:52][C:53]1[CH:54]=[C:55]([N:60]2[C:64](=[O:65])[O:63][N:62]=[C:61]2[C:66]2[C:67]([NH:71][C:72](=O)[C:73](F)(F)F)=[N:68][O:69][N:70]=2)[CH:56]=[CH:57][C:58]=1[F:59].[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81]>O1CCCC1>[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81].[NH2:14][CH2:7][CH2:73][CH2:72][NH:71][C:67]1[C:66]([C:61]2[N:60]([C:55]3[CH:56]=[CH:57][C:58]([F:59])=[C:53]([Cl:52])[CH:54]=3)[C:64](=[O:65])[O:63][N:62]=2)=[N:70][O:69][N:68]=1
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)C(F)(F)F
Reactant: OCCCN=C(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: NCCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
A solution of 3-[(diphenylmethylene)amino]propan-1-ol (80 mg, 0.33 mmol) and triphenylphosphine (93 mg, 0.36 mmol) in tetrahydrofuran (1 mL) at 0° C. was treated with diisopropyl azodicarboxylate (75 μL, 0.38 mmol) dropwise. The reaction mixture was stirred at 0° C. for 15 min, treated with a solution of N-{4-[4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide (100 mg, 0.25 mmol) in tetrahydrofuran (0.5 mL), and stirred at 25° C. for 16 h. The reaction mixture was treated with trifluoroacetic acid (1 mL), stirred at 25° C. for 3 h, and concentrated to a crude residue. This material was purified by preparative LCMS to give the desired product (18 mg, 15%). LCMS for C13H13ClFN6O3 (M+H)+: m/z=355.1
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3]1.Br[CH2:10][CH2:11][CH2:12][OH:13]>C1COCC1>[OH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:3]1
Reactant: OCCCBr
Reactant: OC1CNCC12CC2
Solvent: C1CCOC1
Product: OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.5 %

Procedure:
To a solution of 7-hydroxy-5-azaspiro[2.4]heptane (1.23 g, 11.0 mmol) in THF (40 mL) was added 3-bromopropanol (2.3 g, 16.65 mmol) and Et3N-(2.24 g, 22.2 mmol). The reaction mixture was stirred at rt for 12 hrs and then concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:50:2(v/v/v)EtOAc/CH3OH/Et3N) to afford the desired compound as orange oil (1.14 g, 60%).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]#N.[OH-:13].[K+].C(O)C[OH:17]>>[CH3:1][C:2]([CH3:12])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:17])=[O:13]
Reactant: CC(C)(C#N)Cc1ccccc1
Reactant: OCCO
Reactant: [OH-]
Agent: [K+]
Product: CC(C)(Cc1ccccc1)C(=O)O
Temperature: 196 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
A solution of 2,2-dimethyl-3-phenylpropanenitrile (1.0 g, 6.28 mmol) in ethylene glycol (5 mL) was treated with solid potassium hydroxide (1.06 g, 18.84 mmol). The reaction mixture was stirred for 48 h at 196° C. under a nitrogen atmosphere. Ethylene glycol was removed under vacuum distillation. 1 N Sodium hydroxide solution (25 mL) and ethyl acetate (15 mL) were added to the brown residue. The layers were separated, and the aqueous layer was extracted with ethyl acetate (375 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give 0.856 g (76%) of 2,2-dimethyl-3-phenylpropanoic acid. 1H NMR (DMSO-d6, 400 MHz) δ 12.20 (s, 1H), 7.28-7.24 (m, 2H), 7.22-7.20 (m, 1H), 7.15-7.13 (m, 2H), 2.78 (s, 2H), 1.07 (s, 6H). This compound was used in subsequent reaction with out further analysis.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[F:20][C:21]([F:35])([F:34])[C:22]1([C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][O:33][C:27]=3[CH:26]=2)[O:24][CH2:23]1.Cl>CN(C)C=O.O>[F:35][C:21]([F:20])([F:34])[C:22]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)([OH:24])[CH2:23][O:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: FC(F)(F)C1(c2ccc3c(c2)OCO3)CO1
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OC(COCc1cccc(Oc2ccccc2)c1)(c1ccc2c(c1)OCO2)C(F)(F)F
Temperature: 22 °C
Reaction time: 2 h

Procedure:
3-Phenoxybenzyl alcohol (1.0 g) was added to a stirred suspension of sodium hydride (0.22 g, in the form of 0.44 g of a 50% dispersion in oil) in dry N,N-dimethylformamide (40 cm3), under an atmosphere of nitrogen. The mixture was stirred for a further 2 hours, during which time evolution of hydrogen occurred, and then added dropwise to the epoxide solution prepared in Stage 1. After a further 2 hours stirring at the ambient temperature (ca. 22° C.), the reaction mixture was poured into water, and the aqueous mixture acidified with dilute hydrochloric acid. This mixture was extracted with diethyl ether and the organic layer washed with water, dried over anhydrous magnesium sulphate, and concentrated by evaporation under reduced pressure to give an oil. The oil was purified by column chromatography on a silica gel support, eluting with n-hexane containing 15% by volume ethyl acetate, to give 1,1,1-trifluoro-2-(3,4-methylenedioxyphenyl)-3-(3-phenoxybenzyloxy)propan-2-ol (1.83 g), as a colourless oil.
Reaction SMILES: Cl.[Br:2][C:3]1[N:4]=[C:5]([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]=12.C(N(CC)C(C)C)(C)C.[C:27]([O:30][CH2:31][C:32](Cl)=[O:33])(=[O:29])[CH3:28]>ClCCl>[C:27]([O:30][CH2:31][C:32]([N:15]1[CH2:16][CH2:17][C@@H:13]([C:5]2[N:6]3[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]3=[C:3]([Br:2])[N:4]=2)[CH2:14]1)=[O:33])(=[O:29])[CH3:28]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1nccn2c([C@@H]3CCNC3)nc(Br)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCC(=O)N1CC[C@@H](c2nc(Br)c3c(C)nccn23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To (R)-1-bromo-8-methyl-3-(pyrrolidin-3-yl)imidazo[1,5-a]pyrazine hydrochloride (0.15 mmol, 50 mg) in dichloromethane (4 ml) and N,N-diisopropylethylamine (0.889 mmol, 0.155 ml) at 0° C. was added dropwise a solution of acetoxyacetyl chloride (0.187 mmol, 0.020 ml) in dichloromethane (0.5 ml). After stirring at room temperature for one hour the reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogencarbonate solution, water, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane with gradient 0 to 10% methanol) to give (R)-2-(3-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidin-1-yl)-2-oxoethyl acetate (45 mg).
Reaction SMILES: [Li+].[Cl-].[CH3:3][N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[CH:9]=[N:8][C:7]=2[N:6]([CH3:15])[C:5]1=[O:16].Br[CH2:18][C:19](=[CH2:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([Cu])#N>C1COCC1>[CH3:3][N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9]([CH2:25][C:19](=[CH2:18])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:8][C:7]=2[N:6]([CH3:15])[C:5]1=[O:16]
Reactant: C=C(CBr)C(=O)OCC
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Cc1nc2c(c(=O)n(C)c(=O)n2C)n1C)C(=O)OCC
Temperature: -50 °C
Yield: 68.9 %

Procedure:
TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) was added to a solution of 1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione (12) (194 mg, 1.0 mmol) in THF (2 mL) at 25° C. and the reaction mixture was then stirred at this temperature for max. 5 min. After cooling down to −50 ° C., ethyl 2-(bromomethyl)acrylate (230 mg, 1.2 mmol) and CuCN.2LiCl (1.0 M solution in THF, 5 drops) were added and the resulting mixture was allowed to warm up slowly overnight. The reaction mixture was quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/ether, 1:1) furnished compound 14b (211 mg, 69%) as a colourless solid.
Reaction SMILES: C([C:5]1[C:6]([CH2:23][C:24]([CH2:39][C:40]2[CH:45]=[CH:44][C:43](C(P(OC(C)(C)C)(OC(C)(C)C)=O)(F)F)=[C:42]([Br:61])[CH:41]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:7](C(C)(C)C)[C:8]([Br:18])=[C:9]([C:11]([P:14](=[O:17])([O-:16])[O-:15])([F:13])[F:12])[CH:10]=1)(C)(C)C>CC(O)=O.O>[Br:61][C:42]1[CH:41]=[C:40]([CH2:39][C:24]([CH2:23][C:6]2[CH:5]=[CH:10][C:9]([C:11]([F:13])([F:12])[P:14]([OH:16])([OH:15])=[O:17])=[C:8]([Br:18])[CH:7]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:45]=[CH:44][C:43]=1[O:16][P:14]([CH:11]([F:13])[F:12])(=[O:15])[OH:17]
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(Cc2c(C(C)(C)C)cc(C(F)(F)P(=O)([O-])[O-])c(Br)c2C(C)(C)C)(C(=O)c2ccccc2)c2ccccc2)cc1Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1ccccc1)C(Cc1ccc(OP(=O)(O)C(F)F)c(Br)c1)(Cc1ccc(C(F)(F)P(=O)(O)O)c(Br)c1)c1ccccc1
Yield: 227.7 %

Procedure:
The product of Step 8 (96 mg, 0.094 mmol) was stirred overnight in HOAc (3 mL) and H2O (0.3 mL). The solvent was removed under vacuum and the residue was co-evaporated with toluene/acetone (3×) to give a tan coloured foam (85 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:34][CH2:35][F:36].O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[N:24]([CH2:34][CH2:35][F:36])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: FCCI
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1CCF
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide (100 mg, 0.271 mmol) suspended in acetonitrile (5 ml). Into the mixture, cesium carbonate (124 mg, 0.380 mmol) and 1-Iodo-2-fluoroethane (0.049 ml, 0.596 mmol) were added and the resulting mixture was stirred overnight at RT. Water (2 ml) was added and the mixture was evaporated. The product was purified with LC/MS-trigger. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 2.42 (s, 3H), 4.12-4.23 (m, 2H), 4.30 (dd, 1H), 4.39 (dd, 1H), 4.51-4.61 (m, 1H), 4.58-4.73 (m, 2H), 6.61 (d, 1H), 7.49 (d, 1H), 7.51 (d, 1H), 7.62 (d, 1H), 7.77 (dd, 1H), 7.85 (dd, 1H), 8.00 (dd, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]1>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: CC1(C)CC(CCBr)CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCC3CCOC(C)(C)C3)c2n1
Temperature: 50 °C
Yield: 63.3 %

Procedure:
A mixture of N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate, (0.2 g, 0.571 mmol) and anhydrous potassium carbonate (0.316 g, 2.284 mmol) in DMF (2.5 ml) was heated at 50° C. for 1 hour. The mixture was cooled to room temperature and 4-(2-bromoethyl)-2,2-dimethyltetrahydro-2H-pyran (0.152 g, 0.685 mmol) was added and the mixture heated at 50° C. for 18 hours. The mixture was quenched with water (2 ml) and then extracted with DCM (2×5 ml). The DCM was separated through a hydrophobic frit and evaporated by blowing down under a stream of nitrogen. DMSO:MeOH (1:1) was added to the residue and the resulting precipitate was collected by filtration, washed with methanol and dried in vacuo to give the title compound as a white solid (136 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([NH2:17])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[N:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].[C:30]([C:34]1[C:35]([Cl:43])=[C:36]([C:40](O)=[O:41])[N:37]([CH3:39])[N:38]=1)([CH3:33])([CH3:32])[CH3:31].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([NH:17][C:40]([C:36]3[N:37]([CH3:39])[N:38]=[C:34]([C:30]([CH3:32])([CH3:31])[CH3:33])[C:35]=3[Cl:43])=[O:41])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])[N:9]=2)[CH2:4][CH2:3]1
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)O
Reactant: CN1CCN(c2nc(-c3ccccc3C(F)(F)F)cc(N)c2[N+](=O)[O-])CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CCN(c2nc(-c3ccccc3C(F)(F)F)cc(NC(=O)c3c(Cl)c(C(C)(C)C)nn3C)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-methyl-piperazin-1-yl)-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine (240 mg, 0.630 mmol, prepared as described in the previous step) in THF (10 mL) was treated with NaH (75.6 mg, 1.89 mmol, 60% dispersion in mineral oil) at room temperature for 1 h. At the same time, a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (164 mg, 0.756 mmol, prepared as described in Example B) in DCM (10 mL) was treated with oxalyl chloride (66.0 μL, 0.756 mmol) and DMF (2 drops) at room temperature for 1 h. The resulting mixture was concentrated in vacuo, taken up in THF (6 mL), and added to the sodium anilide solution at room temperature. The solution was stirred at room temperature for 30 min, quenched with saturated aqueous NH4Cl (20 mL), and extracted three times with EtOAc (25 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g SEPRA Si 50 SPE column (Isco system: Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 3:2 v/v for 5 min, then 3:2 to 4:1 v/v over 40 min) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2-(4-methyl-piperazin-1-yl)-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide as an orange solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C26H29ClF3N7O3: 580.2 (M+H); Measured: 580.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[N:7]=[C:6]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:10]=2[CH3:9])[CH:14]=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1ccc(C=O)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C=O)cc1-c1ccnc(Cl)n1
Yield: 80 %

Procedure:
2,4 dichloropyrimidine and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was coupled following procedure A. The yield was 80%. LC-MS showed the product was >95% pure and had the expected M+H+ of 233. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 10.0 (s, 1H) 8.7 (s, 1H) 7.9 (d, 2H) 7.5 (d, 2H), 2.5 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19].CN(C=O)C.Br[CH2:26][CH2:27][Cl:28]>O>[Cl:28][CH2:27][CH2:26][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[C:11]1=[O:19]
Reactant: ClCCBr
Reactant: O=c1[nH]c2ccccc2n1CCOC1CCCCO1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(CCCl)c2ccccc2n1CCOC1CCCCO1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
Into a stirred solution of 1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,3-dihydro-2H-benzimidazol-2-one (6.5 g, 25 mmoles) in DMF (40 ml) 80% sodium hydride (0.9 g, 30 mmoles) was added. After 30 minutes of stirring and heating to 35° C., 1-bromo-2-chloroethane (6.2 g, 48 mmoles) was added, the reaction temperature was increased to 90° C. and kept for 6 hours then cooled at room temperature. The reaction mixture was poured into water, extracted with diethyl ether, and the organic layer was taken to dryness. The residue was purified by flash chromatography (cyclohexane-ethyl acetate 50-50) to give 2.8 g of the title compound as a thick oil which was used without any further purification.