Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH2:6]([O:10][C:11]1[C:16]([F:17])=[C:15](Cl)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26]1([CH3:31])[CH2:30][CH2:29][NH:28][CH2:27]1>C(OCC)(=O)C>[CH2:6]([O:10][C:11]1[C:16]([F:17])=[C:15]([N:28]2[CH2:29][CH2:30][C:26]([CH3:31])([CH3:25])[CH2:27]2)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9]
Reactant: CC1(C)CCNC1
Reactant: CC#CCOc1ncnc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1ncnc(N2CCC(C)(C)C2)c1F
Temperature: 80 °C
Reaction time: 6 h
Yield: 31.7 %

Procedure:
Into 4 ml of N,N-dimethylformamide was resolved 0.36 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine, 0.62 g of potassium carbonate and 0.25 g of 3,3-dimethylpyrrolidine was added therein, and the mixture was stirred for 6 hours at 80° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.15 g of 4-(2-butynyloxy)-5-fluoro-6-(3,3-dimethylpyrrolidin-1-yl)pyrimidine (hereinafter, referred to as Compound (28)).
Reaction SMILES: [CH2:1]([Li])[CH3:2].[F:4][C:5]1[CH:26]=[CH:25][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.[Cl-].[NH4+]>CCOCC>[F:4][C:5]1[CH:26]=[CH:25][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)([OH:10])[CH2:1][CH3:2])=[CH:7][CH:6]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1
Reactant: [Li]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC(O)(c1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1
Temperature: -20 °C

Procedure:
To 125 ml. of a 0.8 molar ethereal ethyl lithium solution a solution of 12.25 g. of 4-fluoro-4'-benzyloxy-benzophenone in 180 ml. of dry ether is added dropwise, in argon atmosphere, with stirring at -20° C. The reaction mixture is allowed to warm up to room temperature and stirred for further 90 minutes. It is then poured into saturated aqueous ammonium chloride solution under cooling. The aqueous phase is extracted with ether, the organic phases are combined and washed to neutral with water. After drying over anhydrous magnesium sulfate ether is distilled off under reduced pressure. The solid residue is crystallized from a mixture of ethyl acetate and n-heptane to yield 7.4 g. of the named compound, melting at 56°-57° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[N:6][CH:7]=1.CC1C=CC(N2C=C3C(C=CC([N+]([O-])=O)=C3)=N2)=NC=1>CCO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(-n2ncc3cc([N+](=O)[O-])ccc32)nc1
Agent: [Pd]
Agent: Cc1ccc(-n2cc3cc([N+](=O)[O-])ccc3n2)nc1
Solvent: CCO
Product: Cc1ccc(-n2ncc3cc(N)ccc32)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The mixture of 1-(5-methylpyridin-2-yl)-5-nitro-1H-indazole and 2-(5-methylpyridin-2-yl)-5-nitro-2H-indazole was dissolved in EtOH (20 mL), and 10% Pd/C (250 mg) was added. Under H2 atmosphere, the mixture was stirred at room temperature for 12 h, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give the title compound as white crystals (76 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]#[N:19])[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O.[NH4+].[Cl-]>CCO.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]#[N:19])[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCS(=O)(=O)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#CC1(c2ccc(N)cc2)CCS(=O)(=O)CC1
Temperature: 50 °C
Yield: 62 %

Procedure:
A suspension of 4-(4-nitro-phenyl)-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carbonitrile (205 mg, 0.731 mmol, as prepared in the previous step) in EtOH (5 mL) and water (5 mL) was treated with solid NH4Cl (204 mg, 3.66 mmol) and Fe powder (392 mg, 7.31 mmol) and heated to 50° C. for 1.5 h. The cooled mixture was filtered through Celite, and the filter cake was washed with MeOH. The solvents were evaporated in vacuo. The residue was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded the title compound (114 mg, 62%) as a pale yellow solid. Mass spectrum (ESI, m/z): Calcd. for C12H14N2O2S, 251.1 (M+H). found 251.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][N:15]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C@H:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:17])[CH2:12][O:11][CH2:10][C@@H:9]1[CH2:35][CH:36]=[CH2:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].C12BC(CCC1)CCC2.CO.B1([O-])O[O:50]1.O.O.O.O.[Na+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH2:35][CH2:36][CH2:37][OH:50])[CH2:10][O:11][CH2:12][C@H:13]1[CH2:14][N:15]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C@H:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [O-]B1OO1
Reactant: C=CC[C@H]1COC[C@@H](CN(C(=O)OCc2ccccc2)[C@@H](C)C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](C(=O)OC(C)(C)C)N(C[C@@H]1COC[C@H](CCCO)N1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80.7 %

Procedure:
To a solution of (3S,5R)-3-allyl-5-{[benzyloxycarbonyl-((S)-1-tert-butoxycarbonyl-ethyl)-amino]-methyl}-morpholine-4-carboxylic acid tert-butyl ester (4.50 g, 8.68 mmol) in tetrahydrofuran (90 mL) was added 9-borabicyclo[3.3.1]nonane solution (0.5 M in tetrahydrofuran, 36.4 mL, 18.2 mmol) at 0° C., then after 21/2 h another portion of 9-borabicyclo[3.3.1]nonane solution (0.5 M in tetrahydrofuran, 20.8 mL, 10.4 mmol) was added. The reaction mixture was stirred for another 45 min at 0° C., then methanol (80 mL), water (115 mL) and sodium perborate tetrahydrate (37.3 g, 242 mmol) were added. After 90 min the ice bath was removed, then after stirring for 16 h the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) afforded the title compound (3.76 g, 81%). Colourless gum, MS: 537.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][OH:25])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([NH:55][C@H:56]([C:60](O)=[O:61])[CH:57]([CH3:59])[CH3:58])([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)C>[CH2:48]([O:47][C:45]([NH:55][C@H:56]([C:60]([O:25][CH2:24][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)=[O:61])[CH:57]([CH3:59])[CH3:58])=[O:46])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CS(=O)(=O)NCCCCn1c(CO)nc2c(N)nc3ccccc3c21
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.8 %

Procedure:
To a stirred suspension of N-[4-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide (2.1 g, 5.8 mmol) in THF was added triphenylphosphine (1.5 equivalents, 8.7 mmol, 2.2 g) followed by CBZ-L-valine (1.5 equivalents, 8.7 mmol, 2.3 g). The suspension was stirred for 5 min after which it was cooled in an ice-bath. To this cooled reaction mixture diisopropyl azodicarboxylate (DIAD, 1.8 equivalents, 10.4 mmol, 2.0 mL) was added and the reaction was warmed to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the crude solid was purified by prep HPLC (ISCO Combiflash Separation System, Biotage Si 40+M column, eluted with a gradient of 0-8% methanol in dichloromethane with 1% ammonium hydroxide) to provide a solid. The solid was heated in diethyl ether and filtered to afford (4-amino-1-{4-[(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-2-yl)methyl N-[(benzyloxy)carbonyl]-L-valinate (2 g) as a beige solid, mp 99-100° C.; MS (ESI) m/z 597 (M+H)+; Anal. Calcd for C29H36N6O6S: C, 58.37; H, 6.08; N, 14.08. Found C, 57.98; H, 6.31; N, 13.82.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](B(O)O)[CH:3]=[N:2]1.[Br:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13](I)=[CH:12][C:11]=1[O:18][CH3:19]>>[Br:9][C:10]1[C:11]([O:18][CH3:19])=[CH:12][C:13]([C:4]2[CH:3]=[N:2][NH:1][CH:5]=2)=[C:14]([Cl:16])[CH:15]=1
Reactant: OB(O)c1cn[nH]c1
Reactant: COc1cc(I)c(Cl)cc1Br
Product: COc1cc(-c2cn[nH]c2)c(Cl)cc1Br
Yield: 72.5 %

Procedure:
Following standard GENERAL METHOD 1-4 for Suzuki coupling using (1H-pyrazol-4-yl)boronic acid (161 mg, 1.44 mmol) and 1-bromo-5-chloro-4-iodo-2-methoxybenzene (500 mg, 1.44 mmol) afforded 4-(4-bromo-2-chloro-5-methoxyphenyl)-1H-pyrazole (300 mg) MS [M+H+]=286.8.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[OH:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=Cc1ccc(-c2ccccc2)o1
Product: COc1ccc(C(O)c2ccc(-c3ccccc3)o2)cc1

Procedure:
The title compound was prepared from the product of step 1 and 4-bromoanisole using the procedure of Example 159, step 2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)(=[O:23])=[O:22]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][CH:5]=[C:4]([NH:30][CH:27]2[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1ccc(Cl)nc1N
Reactant: CS(=O)(=O)N1CCC(N)CC1
Product: COc1ccc(F)cc1C(=O)c1ccc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The title compound was prepared from (2-amino-6-chloropyridin-3-yl)-(5-fluoro-2-methoxyphenyl)methanone (Example 19) and 1-methanesulfonylpiperidin-4-ylamine (Step A. Example 6) using the procedure described in Step B. Example 6. HRMS, observed: 423.1502, Calcd for (M+H)+: 423.1497. Ki for cdk4=0.040 μM, cdk2=0.098 μM, and IC50 for HCT116 cell line=9 μM.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CN=C1.Cl>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Br)n1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCCC(/C=C/c1cccc(Br)n1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
A solution of 4 g of 2-bromo-6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-pyridine in 20 ml of dimethylformamide is mixed with 4.1 g of tert-butyldiphenylsilyl chloride and 2.1 g of imidazole and stirred for 15 hours at room temperature. The reaction mixture is poured into 100 ml of diethyl ether, shaken out twice with 20 ml of 1 n hydrochloric acid, 4 times with 20 ml of saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/0-5% ethyl acetate. 5.5 g of 2-bromo-6[(1E)-(3RS)-3-tert-butyldiphenylsilyloxy-1-undecenyl]-pyridine is obtained as oil.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1.O.[F-].[K+].[Br-].[Na+]>FC(F)(F)C1C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([S:7]([CH2:10][C:11]2[CH:20]=[CH:19][C:18]([C:24]3[CH:25]=[CH:26][O:22][CH:23]=3)=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccoc1
Reactant: COC(=O)c1cc(Br)ccc1CS(=O)(=O)c1ccccc1
Agent: [Pd]
Agent: [Br-]
Agent: [F-]
Solvent: FC(F)(F)c1ccccc1
Solvent: O
Product: COC(=O)c1cc(-c2ccoc2)ccc1CS(=O)(=O)c1ccccc1
Temperature: 175 °C
Yield: 77.2 %

Procedure:
A mixture of methyl 2-benzenesulphonylmethyl-5-bromobenzoate (Intermediate 63, 0.2 g), furan-3-yl boronic acid (0.091 g), tetrakis-(triphenylphosphine) palladium (0.063 g), potassium fluoride monohydrate (0.0.23 g) and sodium bromide (0.1 g) in α,α,α-trifluorotoluene (2.5 ml) was sealed in a microwave vial and the mixture was degassed then heated in the microwave at 175° C. for 30 minutes. After cooling, the mixture was diluted with DCM and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-40% to give methyl 2-(benzenesulphonylmethyl)-5-(furan-3-yl)benzoate (0.149 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][OH:11])=[C:4](F)[CH:3]=1.[H-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:4]=2[CH:3]=1
Reactant: O=C(CO)Nc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2cc(Br)ccc2N1
Temperature: 140 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
A solution of N-(4-bromo-2-fluorophenyl)-2-hydroxyacetamide (8.0 g, 32.3 mmol) in 50 ml dry DMF was added drop wise to a suspension of sodium hydride (5.2 g, 129 mmol) in 30 ml dry DMF and the mixture was stirred for 2 h under an atmosphere of nitrogen at 140° C. After cooling to ambient temperature water was added and the mixture was extracted several times with ethyl acetate. After washing the combined organic layers with brine and drying over MgSO4 the solvent was removed under reduced pressure and the crude product was obtained as a pale yellow solid. Purification by flash chromatography on silica gel (dichloromethane/methanol, 97/3, Rf=0.35) yielded 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (2.3 g, 10.1 mmol, 31%) as off-white solid.
Reaction SMILES: N1C=CN=C1.C(OC([NH:12][C:13]1[CH:49]=[CH:48][C:16]([CH2:17][N:18]2[CH2:22][CH2:21]/[C:20](=[CH:23]\[C:24]3[CH2:31][S:30][C@H:29]4[N:26]([C:27](=[O:43])[C@H:28]4[NH:32][C:33](=[O:42])[CH2:34][S:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:25]=3[C:44]([OH:46])=[O:45])/[C:19]2=[O:47])=[CH:15][CH:14]=1)=O)C=C.C[Si](/N=C(/O[Si](C)(C)C)\C(F)(F)F)(C)C.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC.Cl>ClCCl.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.C(OCC)C>[NH2:12][C:13]1[CH:49]=[CH:48][C:16]([CH2:17][N:18]2[CH2:22][CH2:21]/[C:20](=[CH:23]\[C:24]3[CH2:31][S:30][C@H:29]4[N:26]([C:27](=[O:43])[C@H:28]4[NH:32][C:33](=[O:42])[CH2:34][S:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:25]=3[C:44]([OH:46])=[O:45])/[C:19]2=[O:47])=[CH:15][CH:14]=1
Reactant: C=CCOC(=O)Nc1ccc(CN2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)CSc5ccccc5)[C@H]4SC3)C2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Agent: C[Si](C)(C)/N=C(/O[Si](C)(C)C)C(F)(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1ccc(CN2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)CSc5ccccc5)[C@H]4SC3)C2=O)cc1
Reaction time: 0.25 h

Procedure:
(E)-(6R,7R)-3- [1-(4-allyloxycarbonylamino-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(2-phenylsulfanyl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1) (400.0 mg, 0.57 mmol) was suspended in 20 ml dichloromethane and treated with N,O-bis(trimethylsilyl)-trifluoroacetamide (240.7 ml, 9.11 mmol). After 15 min, bis(triphenylphosphine)palladium(II) chloride (10.0 mg, 0.014 mmol), acetic acid (0.65 ml, 11.4 mmol) and tributyltin hydride (1.53 ml, 5.70 mmol) were added. After 45 min the suspension was poured under stirring on 250 ml diethyl ether, containing 3 ml of a hydrochloric acid-saturated diethyl ether solution and was stirred for 1 h. The solid material was collected by filtration, suspended in 4 ml water: acetonitrile (1:1) and the pH was adjusted to 2 with 1M hydrochloric acid. To the suspension an equal amount of MCI gel (75-150μ, Mitsubishi Kasei Corporation) was added, the organic solvent was evaporated and the residue was chromatographed on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (9:1, 4:1, 2:1, 1:1, 1:3). The organic solvent was evaporated and the aqueous phase was freeze-dried.
Reaction SMILES: S([C:5]1[CH:11]=[CH:10][C:8](C)=[CH:7][CH:6]=1)(O)(=O)=O.[CH3:12][N:13]([CH3:30])[C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([NH:25][C:26]([NH2:28])=[NH:27])=[CH:20][C:19]=2[CH3:29])=[O:15].C[O-].[Na+]>CO>[CH3:12][N:13]([CH3:30])[C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([NH:25][C:26]1[N:28]=[C:7]([C:8]3[N:27]=[CH:26][N:25]([CH3:21])[C:10]=3[CH3:11])[CH:6]=[CH:5][N:27]=1)=[CH:20][C:19]=2[CH3:29])=[O:15]
Reactant: Cc1cc(NC(=N)N)cc2cc(C(=O)N(C)C)[nH]c12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Nc2nccc(-c3ncn(C)c3C)n2)cc2cc(C(=O)N(C)C)[nH]c12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of 42.5 mg 4.5, 80.0 mg 7.7 and 10.8 mg sodium methylate in 2 ml methanol was stirred at 140° C. for 60 min under microwave irradiation. The resulting mixture was purified by preparative HPLC. The combined product fractions were evaporated. The residue was dissolved in acetonitrile/water 1/1 and lyophilized to obtain the Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[CH2:12]([N:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH3:13].C(N(C(C)C)C(C)C)C>ClCCl>[CH2:12]([N:14]1[CH2:20][CH2:19][CH2:18][N:17]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=2)[CH2:16][CH2:15]1)[CH3:13]
Reactant: CCN1CCCNCC1
Reactant: COC(=O)c1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1CCCN(c2ncc(C(=O)OC)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
A solution of methyl 2-chloropyrimidine-5-carboxylate (200 mg, 1.16 mmol) in dichloromethane (4.00 mL) was added to a stirred solution of 1-ethyl-1,4-diazepane (149 mg, 1.16 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.902 mL, 5.22 mmol) in dichloromethane (4.00 mL) at 25° C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 2-(4-ethyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (268 mg, 87%) as a cream oil which crystallised on standing. This was used directly with no further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([OH:10])[C:7]([CH3:11])([CH3:12])[C:6]=2[CH:13]=1
Reactant: CC1(C)C(=O)Oc2ccc(Br)cc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC1(C)c2cc(Br)ccc2OC1O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-Bromo-3,3-dimethyl-3H-benzofuran-2-one (1.199 g, 5.0 mmol) (described in Step 2 of Example A(68), ), dissolved in anhydrous CH2Cl2 (20 ml), and cooled to −78° C., was added DIBAL (3.67 mL, 5.5 mmol, 1.5M in Toluene). The reaction was stirred for 1 h at this temperature then quenched with 1N HCl until acidic. The resulting mixture was extracted with ether, which was washed with brine, dried with MgSO4, concentrated and purified by silica gel chromatography (gradient elution 5–15% Ethylacetate/Hexanes). Yield 0.95 g, 79%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.Cl.[C:22]12([NH2:28])[CH2:27][CH:25]([CH2:26]1)[CH2:24][CH2:23]2>O1CCOCC1.[Cl-].[Na+].O>[C:22]12([NH:28][C:2]3[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=3)[CH2:27][CH:25]([CH2:26]1)[CH2:24][CH2:23]2
Reactant: NC12CCC(C1)C2
Reactant: CSc1ncc(C#N)c(Cl)n1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CSc1ncc(C#N)c(NC23CCC(C2)C3)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (427 mg, 2.3 mmol) in 1,4-dioxane (10 mL) was added DIEA (890 mg, 6.9 mmol) and bicyclo[2.1.1]hexan-1-amine hydrochloride (320 mg, 2.4 mmol). The resulting mixture was stirred at 60° C. for 2 h. The reaction mixture was poured into a saturated brine solution and then extracted with ethyl acetate (20 mL) three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product, which was purified by silica gel column chromatography (15% ethyl acetate in petroleum ether) to give the desired product (502 mg, 2.0 mmol, 89% yield). MS (ESI) m/z=247.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[CH3:17][O:18][C:19](=[O:34])[CH2:20][CH2:21][C:22]1[O:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[N:26]=1>>[CH3:17][O:18][C:19](=[O:34])[CH2:20][CH2:21][C:22]1[O:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:12]3[CH:13]=[C:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[CH3:16])[N:9]=[C:10]([NH2:15])[N:11]=3)=[CH:29][CH:28]=2)[N:26]=1
Reactant: COC(=O)CCc1nc(-c2ccc(N)cc2)co1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Product: COC(=O)CCc1nc(-c2ccc(Nc3cc(-c4cc(Cl)ccc4C)nc(N)n3)cc2)co1

Procedure:
Following the method described in Example 26, 4-(5-chloro-2-methyl-phenyl)-6-chloro-pyrimidin-2-ylamine and 3-[4-(4-amino-phenyl)-oxazol-2-yl]-propionic acid methyl ester provided 3-(4-{4-[2-amino-6-(5-chloro-2-methyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-oxazol-2-yl)-propionic acid methyl ester.