Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([C:8]23[CH2:17][CH2:16][O:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:9]3)[CH:7]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:5]1[CH:4]=[C:3]([F:27])[C:2]([C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)=[CH:7][C:6]=1[C@:8]12[CH2:17][CH2:16][O:15][CH2:14][CH:13]1[CH2:12][S:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:9]2
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc(Br)c(F)cc3F)CCOCC2CS1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(-c4cncnc4)c(F)cc3F)CCOCC2CS1
Temperature: 97 °C
Yield: 86.2 %

Procedure:
A mixture of tert-butyl 8a-(5-bromo-2,4-difluorophenyl)-4,4a,5,7,8,8a-hexahydropyrano[4,3-d][1,3]thiazin-2-ylcarbamate (0.300 g, 0.647 mmol) in 1,2-dimethoxyethane (10 mL), ethanol (4 mL) and water (5 mL) is purged with nitrogen and heated to 97° C. Pyrimidine-5-boronic acid (0.655 g, 5.18 mmol), cesium carbonate (1.90 g, 5.83 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.091 g, 0.129 mmol) is added in a single portion and the reaction is heated at 97° C. for 20 minutes. The reaction is cooled, diluted with water, and extracted with EtOAc. The organic layer is dried over Na2SO4 and the crude product is purified by silica gel chromatography eluting with a linear gradient of 5% to 100% EtOAc in hexanes to give the title compound (0.258 g, 86%). ES/MS (m/e): 463 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:3]=[CH:4][C:5]=1[O:15][CH3:16])=[O:14]
Reactant: COc1ccc(Br)cc1NC(=O)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C#C[Si](C)(C)C)cc1NC(=O)C(F)(F)F
Temperature: 60 °C
Yield: 43.1 %

Procedure:
To an oven-dried flask under N2 was added N-[5-bromo-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (1.53 g, 0.005 mol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)palladium(II) (0.45 g, 0.0006 mol), Cu(I)I (73 mg, 0.38 mmol), and trimethylsilylacetylene (1.26 g, 0.013 mol). Next, TEA (5.19 g, 0.05 mol) was added dropwise and the resulting mixture was heated at 60° C. overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.68 g, 42%) as an off white solid. ESIMS (M−H)−=314.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:24][CH2:25][O:26][CH3:27])=[CH:11][CH:10]=1)C1C=CC=CC=1>O1CCCC1.CO.[Pd]>[CH3:27][O:26][CH2:25][CH2:24][C:16]1[N:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:23]2[C:18]([CH:17]=1)=[CH:19][CH:20]=[CH:21][CH:22]=2
Reactant: COCCc1cc2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COCCc1cc2ccccc2n1-c1ccc(O)cc1
Reaction time: 8 h

Procedure:
1-(4-Benzyloxyphenyl)-2-(2-methoxyethyl)-1H-indole (0.14 g, 0.39 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (1 mL). A catalytic amount of palladium on carbon (wet, 10% dry basis) was added, and the flask was purged with N2 and H2. The reaction was stirred under 1 atm of H2 overnight. The mixture was filtered through Celite, and the filtrate was concentrated to give the desired product. The reaction was assumed to be quantitative. LC-MS (C17H17NO2 calc'd 267) m/z 266 (M−H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[O:23][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A mixture of 2,4-dibenzyloxyphenol (3.1 g) and sodium hydride (0.44 g, 60% dispersion in mineral oil) in THF (75 mL) is refluxed for 30 minutes then refluxing is allowed to abate. Neat ethyl bromoacetate (1.8 g) is added and refluxing continued for 1 hour. The reaction is concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase is washed with water (100 mL), dried o ver magnesium sulphate, filtered and concentrated in vacuo to give a light brown oil. Flash chromatography of the residue eluting with dichloromethane affords ethyl 2,4-dibenzyloxyphenoxyacetate (3.2 g) after trituration with pentane.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:5]=[C:4]([CH3:17])[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:6]2[N:5]=[C:4]([CH3:17])[N:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([Cl:18])=[CH:20][CH:21]=3)[CH:7]=2)[CH:13]=1
Reactant: COc1ccc(Cl)cc1-c1cc(Cl)nc(C)n1
Reactant: Nc1ccc(Cl)cc1
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(Cl)cc2)nc(C)n1
Yield: 61.7 %

Procedure:
Alternatively, a solution of 4-chloro-6-(5-chloro-2-methoxy-phenyl)-2-methyl-pyrimidine (50 mg, 0.18 mmol) and 4-chloroaniline (23 mg, 0.18 mmol) in ethanol (10 ml) was stirred at 80° C. under an argon atmosphere for 5 hours. After concentration under vacuum the crude product was crystallized (ethyl acetate) to give the title compound (40 mg, 60% yield). 1H NMR (DMSO-d6) δ 2.53 (s, 3H, CH3), 3.33 (s, 3H, CH3), 7.23 (d, 1H, J=8.9 Hz, Ar), 7.33 (s, 1H, Ar), 7.41 (d, 2H, J=8.9 Hz, Ar), 7.51 (dd, 1H, J=8.9 Hz, J=2.8 Hz, Ar), 7.79 (d, 2H, J=8.9 Hz, Ar), 8.0 (d, 1H, J=2.8 Hz, Ar), 9.75 (s, 1H, NH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:10]=2[N:9]([CH3:19])[C:8](=[O:20])[CH2:7]1)[CH3:2].[CH2:22]([N:29]=[C:30]=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCOC(C)=O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([NH:18][C:30]([NH:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:31])[CH:16]=[CH:17][C:10]=2[N:9]([CH3:19])[C:8](=[O:20])[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CN1CC(=O)N(C)c2ccc(N)cc2C1=O
Reactant: O=C=NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CC(=O)N(C)c2ccc(NC(=O)NCc3ccccc3)cc2C1=O
Yield: 98.2 %

Procedure:
To a solution of (7-amino-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid ethyl ester (0.65 g, 2.23 mmol) in DMF (5 ml) was added benzylisocyanate (0.5 g, 3.75 mmol) and DMAP (5 mg). After 2 h at 60° C. the reaction mixture was poured into AcOEt (70 ml), washed with aqueous KHSO4 (0.1 N) and water. After drying over Na2SO4 and evaporation of the solvents the residue was purified by chromatography (dichloromethane/MeOH 19:1) to give [7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid ethyl ester (930 mg, 2.19 mmol): mp. 151° C.; MS (EI): 424 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.Cl.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][C:20]=2[N:26]=1.C(N(CC)CC)C.CN(C)C=O>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:23]3[CH2:24][CH2:25][C:19]4[CH:18]=[CH:17][C:16]([Cl:15])=[N:26][C:20]=4[CH2:21][CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Clc1ccc2c(n1)CCNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2ccc(Cl)nc2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 0.03 g (0.12 mmol) 6-bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid, 0.12 mmol 2-chloro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine hydrochloride and 0.51 mmol triethyl amine (TEA) in 1.5 ml dimethylformamide (DMF) 0.14 mmol TBTU (O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate) was added and the reaction mixture was stirred at RT for 1 h. Water was added to the reaction mixture. The precipitate was collected and dried. Yield: 0.018 g (36% of theory). ESI-MS: m/z=406 (M+H)+; Rt(HPLC): 1.29 min. (Method J).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH3:9])=[N:3][CH:2]=1.[OH-].[Li+]>CO.O1CCCC1.O>[N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH3:9])=[N:3][CH:2]=1
Reactant: COC(=O)c1ccc(C(C)Oc2ccncn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(Oc1ccncn1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
To a solution of methyl 4-(1-(pyrimidin-4-yloxy)ethyl)benzoate (0.26 g, 1 mmol) in methanol (5 mL) and tetrahydrofuran (15 mL) was added lithium hydroxide (120 mg, 5 mmol) in water (5 mL), then stirred at room temperature for 5 hours. The reaction mixture was concentrated, the residue was acidified with 6 N hydrochloric acid, by filtration the solid was collected to give-4-(1-(pyrimidin-4-yloxy)ethyl)benzoic acid (0.19 g, 78% yield). LRMS (M+H+) m/z: calcd for 244.08. found 244.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:19][CH:20]([S:24](Cl)(=[O:26])=[O:25])[CH2:21][CH2:22][CH3:23]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:19][CH:20]([S:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:26])=[O:25])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC(C)S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(N)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCC(C)S(=O)(=O)Nc1cccc(OCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl 2-(3-aminophenoxy)ethylcarbamate (3) (210 mg, 1.1 mmol), 2-pentylsulfonyl chloride (4) (0.17 ml, 1.1 mmol) and DMAP (20 mg) in pyridine (5 ml) was stirred at room temperature under argon for 15 hours. The solvent was evaporated under reduced pressure. The residue was partitioned between EtOAc and 0.5 N HCl aq. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (40 to 60% EtOAc-hexanes gradient) gave tert-butyl 2-(3-(1-methylbutylsulfonamido)phenoxy)ethylcarbamate (5) as light yellow oil. Yield (160 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 7.20 (t, J=8.0 Hz, 1H), 6.75-6.82 (m, 1H), 6.73-6.75 (m, 1H), 6.64-6.67 (m, 1H), 6.37 (bs, 1H), 4.96 (bs, 1H), 3.99 (t, J=6.0 Hz, 2H), 3.51 (q, J=6.0 Hz, 2H), 3.11-3.18 (m, 1H), 1.91-2.0 (m, 1H), 1.53-1.60 (m, 2H), 1.44 (s, 9H), 1.23-1.37 (m, 4H), 0.88-0.91 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([CH2:12][CH3:13])=[C:4]([OH:14])[CH:3]=1.[C:15](#[N:17])[CH3:16]>>[Br:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([CH2:12][CH3:13])=[C:4]([O:14][CH2:16][C:15]#[N:17])[CH:3]=1
Reactant: CC#N
Reactant: CCc1c(O)cc(Br)c2c1OCCO2
Product: CCc1c(OCC#N)cc(Br)c2c1OCCO2

Procedure:
8-Bromo-5-ethyl-2,3-dihydro-benzo[1,4]dioxin-6-ol (3.182 g, 12.3 mmol), as described in the procedure of Step 6 of Example 21, was converted to cyanomethyl ether 8-Bromo-5-ethyl-2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-acetonitrile (2.30 g, 63%).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10]C)=[CH:8][CH:7]=[C:6]([I:12])[C:3]=1[C:4]#[N:5].B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([I:12])[C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(I)c(C#N)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#Cc1c(I)ccc(O)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
A −78° C. solution of 2-fluoro-6-iodo-3-methoxybenzonitrile (148 mg, 0.53 mmol) in dichloromethane (5 mL) was treated dropwise with BBr3 (2.5 mL, 1M in dichloromethane, 2.5 mmol), warmed to room temperature, stirred for 18 hours, poured into water, and extracted with diethyl ether. The extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 20% ethyl acetate/hexanes to provide 110 mg of the desired product. MS (ESI(−)) m/e 262 (M−H)−.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5]1)[CH2:2][CH3:3].CN(C1C=CC=CN=1)C.[O:25]1[C:29]([C:30]2[S:34][C:33]([S:35](Cl)(=[O:37])=[O:36])=[CH:32][CH:31]=2)=[CH:28][CH:27]=[N:26]1>O1CCCC1>[CH2:1]([N:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][S:35]([C:33]3[S:34][C:30]([C:29]4[O:25][N:26]=[CH:27][CH:28]=4)=[CH:31][CH:32]=3)(=[O:36])=[O:37])=[CH:13][CH:14]=2)[CH2:5]1)[CH2:2][CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccno2)s1
Reactant: CCCN1CC[C@@H](c2ccc(N)cc2)C1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(-c4ccno4)s3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
4-((S)-1-Propyl-pyrrolidin-3-yl)-phenylamine (100 mg, 0.49 mmol) was dissolved in tetrahydrofuran (5 ml). Subsequently, dimethylaminopyridine (24 mg, 0.20 mmol) and 5-(5-isoxazyl)thiophene-2-sulfonyl chloride (159 mg, 0.64 mmol) were added and the reaction mixture stirred overnight at room temperature. The solvent was evaporated under reduced pressure, the residue treated with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to give the crude product. The crude product was purified with silica gel chromatography with dichloromethane/methanol (100:0 to 96:4) as eluent, yielding the purified product (67 mg, 33%).
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C@@H:6]([C:29]1[CH:37]=[CH:36][C:32]2[CH2:33][CH2:34][O:35][C:31]=2[CH:30]=1)[NH:7][C:8](=[O:28])[CH2:9][N:10]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[CH2:23][CH2:22][CH2:21][NH:20][C:19]=3[N:18]=2)[C:11]1=[O:27])C.[Li+].[OH-]>CCO.O>[O:35]1[C:31]2[CH:30]=[C:29]([C@@H:6]([NH:7][C:8](=[O:28])[CH2:9][N:10]3[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][C:17]4[CH:26]=[CH:25][C:24]5[CH2:23][CH2:22][CH2:21][NH:20][C:19]=5[N:18]=4)[C:11]3=[O:27])[CH2:5][C:4]([OH:38])=[O:3])[CH:37]=[CH:36][C:32]=2[CH2:33][CH2:34]1
Reactant: CCOC(=O)C[C@H](NC(=O)CN1CC[C@H](CCc2ccc3c(n2)NCCC3)C1=O)c1ccc2c(c1)OCC2
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C[C@H](NC(=O)CN1CC[C@H](CCc2ccc3c(n2)NCCC3)C1=O)c1ccc2c(c1)OCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the ester 15-7 (0.038 g, 0.073 mmol) in EtOH/H2O (4.5 mL/0.5 mL) was treated with LiOH (0.009 g, 0.365 mmol) and the homogeneous solution stirred at room temperature for 4 h. The solution was concentrated to a solid residue which was dissolved in H2O and purified by preparative HPLC (gradient conditions: 95:05 to 50:50 H2O/MeCN with 0.1% TFA) to give the acid 15-8 as a white solid (as the bis-trifluoroacetate salt).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][CH:20]([CH2:25][O:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1)([O-])=O.[H][H]>O1CCCC1>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]([CH2:25][O:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22])=[CH:28][CH:29]=1
Reactant: [H][H]
Reactant: COCC(Oc1ccc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1)C(=O)OC
Solvent: C1CCOC1
Product: COCC(Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1)C(=O)OC

Procedure:
A solution of 17 g of 10B in 100 ml of tetrahydrofuran was treated with hydrogen (40 psi hydrogen pressure, Parr-shaker, 10% palladium-on-charcoal catalyst) to give methyl 2-(4-(2-amino-4-(trifluoromethyl)phenylamino)phenoxy)-3-methoxypropionate (10C), as an oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:25]=[C:24]3[C:20]([N:21]=[CH:22][N:23]3[C@H:26]3[C@H:30]([OH:31])[C@H:29]([OH:32])[C@@H:28]([C:33]([NH:35][CH2:36][CH3:37])=[O:34])[O:27]3)=[C:19]([NH:38][CH2:39][CH:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:18]=2)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[Pd+2].[OH-]>[C:41]1([CH:40]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:39][NH:38][C:19]2[N:18]=[C:17]([C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:16])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@H:26]2[C@H:30]([OH:31])[C@H:29]([OH:32])[C@@H:28]([C:33]([NH:35][CH2:36][CH3:37])=[O:34])[O:27]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NC4CCN(Cc5ccccc5)CC4)nc32)[C@H](O)[C@@H]1O
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NC4CCNCC4)nc32)[C@H](O)[C@@H]1O

Procedure:
A solution of N-(1-benzyl-4-piperidinyl)-6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide (Preparation 33) (1.03 g, 1.47 mmol), palladium (II) hydroxide (0.9 g) and ammonium formate (0.46 g, 7.3 mmol) in ethanol (10 ml) was heated under reflux for 3 hours. The catalyst was removed by filtration through Arbocel (trade mark), solvent removed by evaporation under reduced pressure and the residue purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:concentrated aqueous ammonia (90:10:1, by volume) changing to dichloromethane: methanol:concentrated aqueous ammonia (80:20:2, by volume). After evaporation of appropriate fractions the target compound was obtained as a white solid, (0.6 g, 67%).
Reaction SMILES: F[C:2]1[C:7]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:40]([OH:42])[CH3:41]>>[CH2:40]([O:42][C:2]1[C:7]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:41]
Reactant: CCO
Reactant: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3cccnc3F)nc3c2CCC3)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1ncccc1NC(=O)[C@@H]1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a suspension of (S)—N-(2-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (25 mg, 0.053 mmol) in ethanol (1 mL) was added Cs2CO3 (26 mg, 0.080 mmol) and the reaction mixture was allowed to stir at 80° C. for 12 h. The reaction mixture was concentrated, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave an oily residue that was purified by reverse phase HPLC to afford 8 mg of (S)—N-(2-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide as the TFA salt. 1HNMR (400 MHz, CD3OD) δ (ppm): 1.00-1.17 (m, 6H), 1.27 (t, 3H), 2.08-2.30 (m, 4H), 2.36-2.42 (m, 2H), 2.70-2.90 (m, 3H), 2.92-3.03 (m, 2H), 3.60-3.70 (m, 1H), 3.78-3.88 (m, 1H), 4.37 (q, 2H), 4.85-4.95 (m, 1H), 6.24 (s, 1H), 6.82-6.92 (m, 1H), 7.78-7.93 (m, 1H), 8.10-8.18 (m, 1H). The other enantiomer is prepared using the (R) chiral starting material.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([CH3:16])[C:8]2=[NH:17])=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:66]1([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[CH2:72][N:73]1[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:66]1([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[CH2:72][N:73]1[CH2:74][CH2:75][N:76]([C:2]2[CH:19]=[CH:18][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]([CH3:16])[C:8]3=[NH:17])=[CH:4][CH:3]=2)[CH2:77][CH2:78]1
Reactant: c1ccc(-c2ccccc2CN2CCNCC2)cc1
Reactant: Cn1c(=N)n(Cc2ccc(Br)cc2)c2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cn1c(=N)n(Cc2ccc(N3CCN(Cc4ccccc4-c4ccccc4)CC3)cc2)c2ccccc21
Temperature: 95 °C
Reaction time: 0.03 h
Yield: 12.1 %

Procedure:
To a degassed solution of 1-(4-bromo-benzyl)-3-methyl-1,3-dihydro-benzoimidazol-2-ylideneamine (75 mg, 0.237 mmol) in anhydrous toluene (2 ml) was added Pd(OAc)2 (20 mg, 0.047 mmol). Nitrogen was bubbled through the suspension for 10 min before BINAP (29 mg, 0.047 mmol) was added. After a further 2 min 1-biphenyl-2-ylmethyl-piperazine (65 mg, 0.258 mmol) in degassed toluene (2 ml) was introduced and then after a additional 2 min Cs2CO3 (1.54 g, 4.75 mmol) was added and the reaction was stirred for 2 min. Throughout all of the additions nitrogen was continuously bubbled through the reaction mixture. The reaction was then sealed and heated to 95° C. where it was maintained for 16 h. After this time the dark red mixture was cooled to rt and filtered through Celite®. The collected solids were washed with additional toluene and then the combined filtrate and washings were concentrated under reduced pressure to give the crude product. Purification by preparative HPLC provided 1-[4-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-3-methyl-1,3-dihydro-benzoimidazol-2-ylideneamine as a solid (14 mg, 12%). HPLC-MS 488 [M+1]+, 255.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8](O)=[O:9].S(Cl)([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([Cl:14])=[O:9]
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1c(Cl)cncc1Cl
Temperature: 50 °C

Procedure:
3,5-Dichloropyridine-4-carboxylic acid (0.5 g, 2.6 mmol; Reference Example 1) was dissolved in CH2Cl2 (1.75 mL) and DMF (50 μL). Thionyl chloride (0.21 mL; 2.86 mL) was added and the reaction mixture was heated at 50° C. for 20 h. The residue was concentrated in vacuo. The formation of the acid chloride was observed by TLC (50% EtOAc/hexane) and the crude product was carried on to the next step.