Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[CH3:13][O:14][CH2:15][CH2:16]Br.C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH2:15][O:14][CH3:13])[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: OCCNCc1ccc(Cl)nc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(CCO)Cc1ccc(Cl)nc1
Temperature: 95 °C
Yield: 58.6 %

Procedure:
A stirred mixture of 6.0 grams (0.03 mole) of 2-{[(6-chloro(3-pyridyl))methyl]amino}ethan-1-ol (known compound), 4.6 grams (0.033 mole) of 2-bromoethyl methyl ether and 5.8 grams (0.045 mole) if diisopropylethylamine in 120 mL of 1,4-dioxane was heated at 95° C. for 36 hours. After this time the reaction mixture was cooled to ambient temperature and was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, eluting with a mixture of methanol and methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure, yielding 4.3 grams of 2-{[(6-chloro(3-pyridyl))methyl](2-methoxyethyl)amino}ethan-1-ol as an oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[N:24](COCC[Si](C)(C)C)[C:23]4[C:22](=[O:33])[N:21]([CH3:34])[C:20](=[O:35])[N:19]([CH3:36])[C:18]=4[N:17]=3)[CH:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1.Cl>CCO>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[NH:24][C:23]4[C:22](=[O:33])[N:21]([CH3:34])[C:20](=[O:35])[N:19]([CH3:36])[C:18]=4[N:17]=3)[CH:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(=O)c2c(nc(-c3cnn(CC#Cc4cccc(F)c4)c3)n2COCC[Si](C)(C)C)n(C)c1=O
Agent: Cl
Solvent: CCO
Product: Cn1c(=O)c2[nH]c(-c3cnn(CC#Cc4cccc(F)c4)c3)nc2n(C)c1=O
Temperature: 80 °C

Procedure:
8-{1-[3-(3-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1,3-dimethyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.100 g, 0.19 mmol) in EtOH (5 mL) was treated with 2N HCl (1.1 mL) and heated at 80° C. for 2 hrs. The reaction mixture was concentrated in vacuo, and the residue was triturated with diethyl ether to afford 8-{1-[3-(3-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1,3-dimethyl-3,7-dihydro-purine-2,6-dione in (0.040 mg, 54%) as a white solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]([CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])[OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[O:17]=[P:18]12[O:29]P3(OP(OP(O3)([O:25]1)=O)(=O)[O:19]2)=O>>[C:1]([O:6][CH2:7][CH:8]([CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])[OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[P:18]([O-:29])([O-:25])([O-:19])=[O:17]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: C=C(C)C(=O)OCC(O)COC(=O)C(=C)C
Product: O=P([O-])([O-])[O-]

Procedure:
Reaction of 72 g glycerol-1,3-dimethacrylate with 17 g phosphorous pentoxide was performed under stirring, cooling with an ice bath and nitrogen atmosphere at room temperature for 48 hours to yield glycerol-1,3-dimethacrylate phosphate as a pale yellow liquid. The product was characterized by 1H- and 31P-NMR spectroscopy.
Reaction SMILES: [C:1]1([C@@H:7]([OH:16])[C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1.C1C=CC=CC=1.O>CCOCC.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.CCCCCC>[C:1]1([C@@H:7]2[C@@H:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:22]3([CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]3)[O:16]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O[C@H](c1ccccc1)[C@H](O)c1ccccc1
Reactant: O=C1C=CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: C1=CC2(CCC1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Temperature: 115 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a 2 L flask was added (1R,2R)-1,2-diphenyl-1,2-ethanediol (200 g, 924 mmol), 2-cyclohexen-1-one (101 g, 1017 mmol), benzene (1232 mL) and PPTS (11.61 g, 46.2 mmol). The flask was fitted with a condenser and a dean-stark trap filled with benzene. The reaction was heated to 115° C. for 18 h (meanwhile trap contained 16.8 mL water indicating reaction completion). The reaction was cooled to RT and diluted with ether. The mixture was washed with saturated aq NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated to give an orange liquid. This was passed over a silica gel plug eluting with 100% hexane (500 mL), then 5% EtOAc/Hexane (2 L), then 10% EtOAc/Hexane (500 mL), then 25% EtOAc/Hexane (500 mL). The product eluted in the first ˜2.5 L of solvent. Removal of solvent afforded a light yellow oil. To this residue was added ˜275 mL of hexane and the solution was let stand and crystals started to rapidly form. After about 1 h at RT, the solution was cooled in the freezer overnight. The next day, the hexane was decanted off, the solids washed with cold hexane. The solids were dried under reduced pressure at 75° C., and 223.75 g of (2R,3R)-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-6-ene was obtained. The hexane solution was concentrated and purified by silica gel (ISCO, 330 g column, 100 mL/min, 0-10% EtOAc/Hexane over 40 min). Concentration of the pure fractions afforded (2R,3R)-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-6-ene as an oil that solidified on sitting (30.47 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([O:23][CH3:24])=[CH:21][C:20]([NH2:25])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([O:23][CH3:24])=[CH:21][C:20]([NH:25][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ncc(N)cc3OC)cc2)CC1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC1CCC(c2ccc(-c3ncc(Nc4ccccc4)cc3OC)cc2)CC1
Reaction time: 18 h

Procedure:
To a solution of {4-[4-(5-Amino-3-methoxy-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.12 g, 0.3 mmol, 1.0 equiv) and phenyl boronic acid (0.082 g, 0.67 mmol, 2.0 equiv) in 5 Ml dichloromethane was added pyridine (0.054 Ml, 0.67 mmol, 2.0 equiv), copper (II) acetate (0.092 g, 0.50 mmol, 1.5 equiv), and 4 Å molecular sieves. The heterogeneous reaction mixture was allowed to stir open to atmosphere for 18 h. Removal of solvent and purification by silica gel chromatography (40% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.31 (m, 2 H) 1.50 (br. S., 1 H) 1.55 (dd, J=12.51, 2.40 Hz, 2 H) 1.87 (d, J=12.38 Hz, 5 H) 2.31 (d, J=6.57 Hz, 2 H) 3.66 (s, 3 H) 3.86 (s, 3 H) 6.96 (t, J=7.33 Hz, 1 H) 7.20-7.38 (m, 7 H) 7.82 (d, J=8.34 Hz, 2 H) 8.11 (d, J=2.02 Hz, 1 H) 8.53 (s, 1 H); (M+H)+ 431.2.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:38])[N:15]=[C:16]([NH:17][CH2:18][C@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[C:20]([O:22]C(C)(C)C)=[O:21])[C:11]=2[CH:10]=[CH:9]1)C.C([O-])C.[Na+].[NH2:44][C:45]1[NH:46][CH2:47][CH2:48][CH2:49][N:50]=1>C1COCC1>[CH2:31]([O:30][C:28]([NH:27][C@@H:19]([CH2:18][NH:17][C:16]1[C:11]2[CH:10]=[CH:9][N:8]([CH2:7][CH2:6][CH2:5][C:4](=[O:3])[NH:44][C:45]3[NH:50][CH2:49][CH2:48][CH2:47][N:46]=3)[C:12]=2[N:13]=[C:14]([CH3:38])[N:15]=1)[C:20]([OH:22])=[O:21])=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NC1=NCCCN1
Reactant: CCOC(=O)CCCn1ccc2c(NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)nc(C)nc21
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 300 mg (0.5 mmol) of 4-[4-((2S)-2-benzyloxycarbonylamino-2-tert-butoxycarbonyl-ethylamino)-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-butyric acid ethyl ester (example 2b) in 5 ml of absol. THF were added 124 mg (1.82 mmol) of sodium ethanolate and 155 mg (1.56 mmol) of 1,4,5,6-tetrahydro-2-aminopyrimidine and the solution was stirred at room temperature for 6 hours. The mixture was brought to pH 7.0 and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with DCM/MeOH/AcOH/H2O (90:10:1:1). Yield: 28 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[C:8]2[S:14][CH:13]=[C:12]([CH3:15])[C:9]=2[NH:10][CH:11]=1)=[O:5])[CH3:2].P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[S:14][CH:13]=[C:12]([CH3:15])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(C)csc2c1=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(C)csc2c1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
A mixture of 3-methyl-7-oxo-4,7-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (WO 2003/059878 A2) (1.0 g) and phosphorus oxychloride (3 mL) was heated at 150° C. for 15 minutes in a microwave reactor. The reaction mixture was then cooled and poured into a mixture of ice-water and ethyl acetate. The resulting mixture was stirred for 10 minutes; the organic layer was separated, washed twice with water (50 mL) and with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. To the solid residue dissolved in a mixture of ethyl acetate and isopropanol (10/1, 55 mL) sodium acetate trihydrate (2.0 g) and palladium hydroxide on carbon (20%, 0.3 g) were added and the resulting mixture was shaken in a Parr apparatus under hydrogen atmosphere (50 PSI) overnight. The reaction mixture was then filtered on a CELITE™ pad, the filtrate was evaporated under reduced pressure and the crude residue was purified by flash chromatography (EtOAc/hexane, 10/90) to afford 0.78 g of 3-methyl-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([C:26]([NH:28]O)=[NH:27])=[CH:23][CH:24]=4)[CH:19]=[CH:18]3)=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].[H][H]>CO.[C].[Pd]>[F:33][C:31]([F:32])([F:34])[C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:30])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([C:26]([NH2:28])=[NH:27])=[CH:23][CH:24]=4)[CH:19]=[CH:18]3)=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: N=C(NO)c1ccc2c(ccn2-c2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N=C(N)c1ccc2c(ccn2-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c1
Yield: 27.4 %

Procedure:
In 10 mL of methanol, 12 mg (0.025 mmol) of 1-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-N-hydroxy-1H-indole-5-carboxamidine was dissolved and the solution was subjected to hydrogenation catalytic reduction on 10% palladium carbon in a hydrogen atmosphere at room temperature for 14 hours. After removal of the palladium carbon by a membrane filter, the filtrate was concentrated under reduced pressure, and the obtained product was triturated from diethyl ether to obtain 3 mg (25%) of 1-{4-[3-(3-(trifluoromethyl)phenyl)-ureido]phenyl}-1H-indole-5-carboxamidine (Table 1, Compound No. 25).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: C1CCNC1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCCC4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and pyrrolidine. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.79-1.95 (m, 4H) 2.33 (d, J=2.44 Hz, 3H) 3.49 (t, J=5.61 Hz, 4H) 7.42-7.82 (m, 2H) 7.84-8.76 (m, 4H). ESI-MS m/z [M+H]+392.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23](OS(C)(=O)=O)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([N:37]=[N+:38]=[N-:39])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](N=[N+]=[N-])CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(cis-4-methanesulfonyloxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (1.16 g, 2.00 mmol) in 10 ml of DMF is added sodium azide (0.65 g, 10 mmol). The reaction mixture is stirred for 48 h at 50° C. The mixture is diluted with ethyl acetate, washed 3 times with water and 1 time with brine. The organic layer is dried with sodium sulfate, filtered and concentrated under reduce pressure to give 3-[(trans-4-azido-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@H:25]3[CH2:29][NH:28][CH2:27][C@H:26]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CN(C)C=O.CCN(C(C)C)C(C)C>[CH3:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@H:25]3[CH2:29][N:28]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:27][C@H:26]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CNC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(S(C)(=O)=O)C[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To the stirred solution of 373 mg of tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylate hydrochloride in 8 mL of N,N-dimethylformamide and 0.5 mL of Hunig's base was slowly added 104 mg of methanesulfonyl chloride. The solution was stirred at room temperature overnight. After removal of the N,N-dimethylformamide in vacuo, the residue was dissolved in 80 mL of ethyl acetate. The ethyl acetate solution was washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexane to provide 233 mg of tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]-1-(methylsulfonyl)pyrrolidine-3-carboxylate in 58% yield. MS: 576.1 (M+H)+
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:12]([O:18][CH2:19]Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[N:6]([CH2:19][O:18][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=O)[nH]1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Mn+4]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1ncc(C=O)n1COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A suspension of 2-butylimidazol-5-aldehyde (16,92 g, 0.111 mol, prepared by manganese dioxide oxidation of the alcohol, prepared in Example 1,Method 2), chloromethyl pivalate (21.77 g, 0.145 mol), and potassium carbonate (20.07 g, 0.145 mol) in 200 ml of dimethylformamide was stirred at ambient temperature under argon for four days. The solids were removed by filtration and washed with ether. The combined filtrates were partitioned between diethyl ether and water. The ether phase was washed successively with water and brine, dried over magnesium sulfate and concentrated under vaccum to give 23.6 g of 2-n-butyl-1-pivalyloxymethylimidazole-5-aldehyde.
Reaction SMILES: [OH-].[NH3+]N.[NH2:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH:8]=[C:7]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[C:31]([C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)[CH:32]=3)[NH:27][CH:26]=2)[N:6]=1>CO>[NH2:14][CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[C:7]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[C:31]([C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)[CH:32]=3)[NH:27][CH:26]=2)[N:6]=[C:5]([NH2:4])[N:10]=1
Reactant: Cn1cc(-c2cnc3[nH]cc(-c4cc(CCCN5C(=O)c6ccccc6C5=O)nc(N)n4)c3c2)cn1
Agent: N[NH3+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(-c2cnc3[nH]cc(-c4cc(CCCN)nc(N)n4)c3c2)cn1
Temperature: 60 °C

Procedure:
8.6 0.003 ml (0.06 mmol) of hydrazinium hydroxide is added at RT to a solution of 29 mg (0.06 mmol) of 2-(3-{2-amino-6-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl}pyrimidin-4-yl]propyl)isoindole-1,3-dione in 0.5 ml of methanol. The reaction solution is heated for 5 min at 60° C. in the microwave. The reaction mixture is evaporated in vacuo, and the residue is purified by preparative HPLC, giving 4-(3-aminopropyl)-6-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-2-ylamine as yellow solid, ESI 349
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][C:10]=2[O:17]C)=[C:4]([F:22])[CH:3]=1>Br.C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc(SC)ccc1C(=O)NCc1ccc(Br)cc1F
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSc1ccc(C(=O)NCc2ccc(Br)cc2F)c(O)c1
Temperature: 100 °C
Yield: 47.2 %

Procedure:
A solution of N-(4-bromo-2-fluoro-benzyl)-2-methoxy-4-methylsulfanyl-benzamide (11 g crude, from step 1) was dissolved in a 25% HBr in glacial acetic acid solution (400 mL) and heated to 100° C. for 4 h. The solution was diluted with ethyl acetate (750 mL) and washed with saturated NaCl (500 mL). The organic layer was dried over MgSO4, filtered and concentrated. Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min) gave N-(4-bromo-2-fluoro-benzyl)-2-hydroxy-4-methylsulfanyl-benzamide (5.0 g, 50%). Rf 0.57 (40% ethyl acetate in heptane); 1H NMR (DMSO-d6 300 MHz) δ 12.57 (s, 1 H), 9.22 (t, J=5.4 Hz, 1 H), 7.78 (d, J=8.4 Hz, 1 H), 7.52 (dd, J, =9.8 Hz, J2=1.7 Hz, 1 H), 7.40–7.27 (m, 2 H), 6.77–6.71 (m, 2 H), 4.46 (d, J=5.7 Hz, 2 H), 2.46 (s, 3 H).
Reaction SMILES: C([N:8]1[CH:12]([CH:13]2[CH2:16][CH2:15][CH2:14]2)[CH2:11][C:10](=[O:17])[O:9]1)C1C=CC=CC=1.[H][H]>C(O)C.O[Pd]O>[NH2:8][CH:12]([CH:13]1[CH2:16][CH2:15][CH2:14]1)[CH2:11][C:10]([OH:17])=[O:9]
Reactant: [H][H]
Reactant: O=C1CC(C2CCC2)N(Cc2ccccc2)O1
Agent: O[Pd]O
Solvent: CCO
Product: NC(CC(=O)O)C1CCC1

Procedure:
Dihydroxypalladium (0.252 g, 1.794 mmol) was charged into a flask and flushed with nitrogen. Ethanol (30 mL) was added followed by a solution of 2-benzyl-3-cyclobutyl-isoxazolidin-5-one, 47a, (0.834 g, 3.605 mmol) in approximately 90 mL of ethanol. The reaction mixture was subjected to 50 psi of hydrogen for 4 hours. The pressure was vented and the catalyst was filtered off. All volatiles were removed at reduced pressure. 1H NMR shows the presence of starting material, 47a. The mixture was dissolved in approximately 100 mL of MeOH and added to 83 mg of 10% Pd/C that had been wet with 20 mL of MeOH. The mixture was subjected to 50 psi of H2 overnight. The pressure was vented and the catalyst was filtered off. All volatiles were removed at reduced pressure to afford 340 mg of product. The resulting crude residue was used without further purification: 1H NMR (400 MHz, d6-DMSO) δ 3.06-2.83 (m, 1H), 2.28 (ddd, J=23.7, 11.8, 7.7 Hz, 1H), 2.19-1.99 (m, 2H), 1.99-1.56 (m, 6H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[CH2:12]([O:14][C:15](=[O:31])/[CH:16]=[C:17](/[O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[CH3:30])\[CH2:18]Br)[CH3:13].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([NH:6][CH2:18]/[C:17](/[O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[CH3:30])=[CH:16]\[C:15]([O:14][CH2:12][CH3:13])=[O:31])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc2c1cnn2C
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)/C=C(\CN[C@@H](CC(C)C)C(=O)OC)Oc1cccc2c1cnn2C
Temperature: 90 °C
Yield: 62 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.043 g, 0.24 mmol), (E)-4-bromo-3-(1-methyl-1H-indazol-4-yloxy)-but-2-enoic acid ethyl ester (0.073 g, 0.22 mmol) and N,N-diisopropylethylamine (0.070 g, 0.54 mmol) in acetonitrile (6 mL) in a sealed tube was heated at 90° C. for 18 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0% to 100% diethyl ether/hexanes) to afford (S)-2-[(E)-3-ethoxycarbonyl-2-(1-methyl-1H-indazol-4-yloxy)-allylamino]-4-methyl-pentanoic acid methyl ester (0.055 g, 66%).
Reaction SMILES: C([NH:4][C:5](=[O:11])[CH2:6][S:7][C:8](=[O:10])[CH3:9])(=O)C.[OH-].[Na+].[O:14]1C=[CH:17][CH:16]=[C:15]1C(Cl)=O>CO>[O:14]1[CH:15]=[CH:16][CH:17]=[C:9]1[C:8]([S:7][CH2:6][C:5]([NH2:4])=[O:11])=[O:10]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(=O)NC(=O)CSC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)CSC(=O)c1ccco1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A slurry was prepared from 8.75 g. (0.05 mole) of N-acetyl-2-(acetylthio)acetamide and 100 ml. of methanol at -5° C., and nitrogen was bubbled through the slurry. There was then added 2.0 g. (0.05 mole) of sodium hydroxide in 20 ml. of methanol. The reaction mixture was aged for 1 hour and then concentrated under high vacuum while the temperature was kept below 30° C. Next, 100 ml. of dimethylformamide was added and the reaction mixture was cooled to 0° C. There was then added 7.2 g. (0.055 mole) of 2-furoyl chloride, and the reaction mixture was aged for 3 hours at 0° C., after which it was concentrated under high vacuum. The residue was charged to a silica gel column and eluted with 50% ethylacetate/hexane. The product was recrystallized from toluene and air dried to yield 2.9 g., m.p. 126°-128° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[C@@H:10]([OH:16])[CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[C:10](=[O:16])[CH2:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CC2CCC1N(Cc1ccccc1)C2
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=C1CC2CCC1N(Cc1ccccc1)C2
Yield: 80.8 %

Procedure:
To a vigorously stirring suspension of (6S)-N-benzyl-2-azabicyclo[2.2.2]octan-6-ol (1.5 g, 6.9 mmol, Maybridge) and activated 4 Å MS (1.0 g) in acetonitrile (70 mL) at 23° C. was sequentially added 4-methylmorpholine-N-oxide (1.2 g, 10 mmol) and tetrapropylammonium perruthenate (240 mg, 0.69 mmol). After stirring the resulting black suspension for 30 min, the mixture was concentrated in vacuo, and the resulting residue was purified by flash chromatography (20-50% ethyl acetate in hexanes) to provide N-benzyl-2-azabicyclo[2.2.2]octan-6-one as an orange oil (1.2 g, 81%). MS (AP CI) 216 (M+H).