Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C1(C)C=CC=CC=1>[C:19]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:22])[CH:20]=[CH2:21]
Reactant: Oc1cccc2cccnc12
Reactant: C=CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1cccc2cccnc12
Reaction time: 8 h

Procedure:
8-Hydroxyquinoline (58.0 g: 0.40 mole) was dissolved in a mixture of toluene (500 ml) and triethylamine (41.4 g; 0.41 mole). Acrylyl chloride (38.0 g; 0.42 mole) was added slowly, while stirring, the reaction temperature beting kept under 30° C. When the addition was complete the mixture was stirred for another 1 hour. The solution was then filtered and washed with a solution of sodium hydrogen carbonate in water followed by water only, and finally the toluene layer was dried with anhydrous sodium sulphate. Some toluene was evaporated off using a rotary evaporator under low pressure. The solution was left in a refrigerator overnight and the solid formed was filtered off. This was identified by infra-red and N.M.R. spectroscopy and microanalysis to be 8-quinolinyl acrylate. Yield 48.6 g (61 percent of the theoretical yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[C:11]1[CH:33]=[N:32][C:14]2[N:15]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]3[CH:21]=[N:20][C:19]([C:22]#[N:23])=[CH:18][C:17]=3[C:13]=2[CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1>[N:1]1([C:11]2[CH:33]=[N:32][C:14]3[N:15]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:16]4[CH:21]=[N:20][C:19]([C:22]#[N:23])=[CH:18][C:17]=4[C:13]=3[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(Br)cnc21
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(N3CCc4ccccc43)cnc21
Temperature: 110 °C
Yield: 54 %

Procedure:
Indoline (67 mg, 0.56 mmol) was added to a solution of 3-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (210 mg, 0.52 mmol), tribasic potassium phosphate (164 mg, 0.77 mmol) and dicyclohexyl-(2′,6′-diisopropoxy-biphenyl-2-yl)-phosphane (88 mg, 0.19 mmol) in anhydrous toluene (5.0 mL). The reaction mixture was degassed with nitrogen for 10 minutes, heated at 110° C. for 18 h and then allowed to cool to ambient temperature. The resultant mixture was poured into water (40 mL) and extracted with DCM (2×40 mL). The combined organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica, 12 g column, ISCO, 0-40% ethyl acetate in cyclohexane) and the isolated solid triturated with diethylether/pentane and air dried to afford the title compound as a yellow powder (124 mg, 54%). LCMS (Method B): RT=4.83 min, M±H+=442.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[N:6]1([S:12]([C:15]2[CH:16]=[C:17]([CH2:21]O)[CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:3][CH2:21][C:17]1[CH:16]=[C:15]([S:12]([N:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(c1cccc(CO)c1)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc(CCl)c1)N1CCCCC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Phosphorus oxychloride (1.00 mL) was added to DMF (5.0 mL), and stirred at 80° C. for 30 minutes. A solution prepared by dissolving [3-(piperidin-1-ylsulfonyl)phenyl]methanol (2.00 g) obtained in Reference Example 21 in DMF (5.0 mL) was added to it, and stirred at 80° C. for 30 minutes. At 0° C., aqueous saturated sodium carbonate solution was added thereto, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 50%, gradient) to give the entitled compound (1.26 g, 59%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][OH:26])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[K+].Br[CH2:29][C:30]1[O:31][C:32](=[O:36])[O:33][C:34]=1[CH3:35].C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][OH:26])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH2:29][C:30]4[O:31][C:32](=[O:36])[O:33][C:34]=4[CH3:35])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Cc1oc(=O)oc1CBr
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OCc2oc(=O)oc2C)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Yield: 26.5 %

Procedure:
To a solution of potassium 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.0 g) in N,N-dimethylacetamide (30 ml) was added 4-bromomethyl-5-methyl-1,3-dioxol-2-one (1.0 g) under ice-cooling with stirring. The reaction mixture was stirred at the same temperature for 30 minutes. The resulting mixture was poured into ethyl acetate (200 ml) and the organic solution was washed with water three times. The separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (50 g) to give (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (0.62 g).
Reaction SMILES: [OH:1]C1C=CC(C=O)=CC=1C.C([O-])([O-])=O.[K+].[K+].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=1.O>CN(C=O)C>[NH4+:19].[OH-:1].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=1
Reactant: Cc1cc(C=O)ccc1O
Agent: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: [NH4+]
Product: [OH-]
Yield: 0.7 %

Procedure:
A solution of 4-hydroxy-3-methylbenzaldehyde (1.0 equiv) in DMF (0.2 M solution) was treated with K2CO3 (1.5 equiv) and 6-chloronicotinamide (1.0 equiv). The reaction mixture was placed inside the microwave oven and then irradiated for 5 min. Upon completion of the reaction, the mixture was cooled, poured into H2O and extracted with ethyl acetate, and the combined organic layers were washed twice with water and brine. After drying the extracts over magnesium sulfate and evaporation under vacuum the crude product was purified by silica eel chromatography using CHCl3:EtOH 7%:NH4OH 0.7% to afford the title compound as a solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][NH:13]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:27][C:28]([NH:36][CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=1[O:32][CH3:31])=[O:29]
Reactant: O=C(Br)CBr
Reactant: COc1ccccc1CN
Reactant: COc1cc2c(cc1OC)C(Cc1ccc3ccccc3c1)NCC2
Product: COc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC)cc2C1Cc1ccc2ccccc2c1

Procedure:
prepared by reaction of 1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methoxy-benzyl-amine
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([N:12]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:14](I)=[CH:13]1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:39]=1)[C:33](N(OC)C)=[O:34]>C1COCC1>[Br:27][C:28]1[CH:39]=[C:32]([C:33]([C:14]2[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:12]([C@@H:10]([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:13]=2)=[O:34])[CH:31]=[N:30][CH:29]=1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnccc21
Reactant: CON(C)C(=O)c1cncc(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(Br)c2)c2cnccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine (Preparation 55, 16 g, 38.6 mmol) in THF (340 mL) was added iPrMgCl (23.2 mL, 46.3 mmol, 2M solution in THF) dropwise at 0° C. After stirring at this temperature for 1 hour, a solution of 5-bromo-N-methoxy-N-methylnicotinamide (11.4 g, 46.3 mmol) in THF (40 mL) was added slowly to the reaction. The reaction was warmed at room temperature and stirred for 18 hours. The reaction was quenched by the addition of water (200 mL) and the solvents removed in vacuo. The residue was diluted with water (400 mL), extracted into DCM:MeOH (95:5, 200 mL)) five times, the organic layers collected, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a gradient of 10-50% EtOAc in DCM to afford the title compound (18.3 g, 46.5%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=O)=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+].[C:28](O)(=[O:30])[CH3:29]>>[C:28]([O:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([CH3:22])=[CH:17][CH:16]=2)(=[O:20])=[O:21])[CH2:2][CH:3]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1CCNc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)OC1=CCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc21

Procedure:
1,2,3,4-Tetrahydroquinolin-4-one (2.00 g) and 114 mg of p-toluenesulfonic acid were dissolved in 30 ml of acetic acid isopropenyl ether, and the solution was heated under reflux for 2 days simultaneously evaporating acetic acid. Then, saturated sodium bicarbonate aqueous solution was added and the mixture was extracted with ethyl acetate, followed by drying on anhydrous magnesium sulfate. After evaporating the solvent, the resulting residue was crystallized from chloroform-diethyl ether-hexane to obtain 518 mg of 4-acetoxy-1-tosyl-1,2-dihydroquinoline.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[N+:11]([O-])([OH:13])=[O:12].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c2ncccc12
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1n[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 25 °C

Procedure:
3-Methyl-pyrazolo[3,4-b]pyridine (1 Mmol, 1 eq.) was suspended into a mixture of 1:1 fuming nitric acid and concentrated sulfuric acid (1 mL:1 mL), and the resultant mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled to rt, and poured into a mixture of sodium bicarbonate and ice. The resultant solution was warmed up to rt and extracted with 300 mL of EtOAc. The organic extract was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography to provide 70.2 Mg of 3-methyl-5-nitro-pyrazolo[3,4-b]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:34]2[CH2:33][CH2:32][CH:31]([C:28]3[CH:29]=[CH:30][C:25]([OH:24])=[CH:26][CH:27]=3)[CH2:36][CH2:35]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: Oc1ccc(C2CCNCC2)cc1
Product: CN1C(=O)c2ccccc2C1C(CCN1CCC(c2ccc(O)cc2)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 139.7 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.378 g) was coupled to 4-(4-hydroxy-phenyl)piperidine (0.191 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in Example 8 to afford the title compound (0.414 g); mp 150°-160° C.; MS: m/z=508(M+1); NMR(CD3SOCD3): 1.93-2.06 (m,4), 2.65-2.73 (m,3), 3.06 (s,3), 3.35 (m,4), 3.6-3.7 (m,3), 4.87 (d,1, J=3.5), 6.7-6.8 (m,3), 6.9-7.0 (m,3), 7.32 (d,1, J=8.3), 7.50 (s,2), 7.64 (m,1), 7.95 (d,1, J=7.7). Analysis for C29H30Cl2N2O2.1.0 HCl.1.0 H2O: Calculated: C, 61.87; H, 5.73; Found: C, 62.13; H, 5.94.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15]Cl)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:27]([C:34]1([OH:40])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH2:27]([C:34]1([OH:40])[CH2:39][CH2:38][N:37]([CH2:15][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:19])[CH3:18])=[CH:8][CH:9]=2)=[O:17])[CH2:36][CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CCl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CN2CCC(O)(Cc3ccccc3)CC2)cc1
Yield: 76.4 %

Procedure:
N-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-2-chloro-acetamide (1.14 g, 3.8 mmol) was dissolved in dimethylformamide (DMF) (12 ml) and stirred for 19 hours at room temperature in the presence of triethylamine (0.79 ml, 5.7 mmol) and 4-benzyl-4-hydroxypiperidin (0.87 g, 4.56 mmol). The reaction mixture was concentrated, dissolved in CH2Cl2 and washed with H2O (2×30 ml). The organic phase was dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ethyl acetate 1:1 then ethyl acetate) to provide 2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-N-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acetamide (1.32 g, 78%) as a yellow solid, m.p. 105°-108° C. and MS: m/e=455.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21]O)[N:20]=[C:15]2[CH:14]=1.O=S(Cl)Cl.[N-:36]=[N+:37]=[N-:38].[Na+].CN(C=O)C>C(Cl)Cl>[N:36]([CH2:21][C:19]1[N:20]=[C:15]2[CH:14]=[C:13]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:8]([CH3:12])[CH:7]=3)[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:16]2=[N:17][CH:18]=1)=[N+:37]=[N-:38]
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CO)cnc3n1COCC[Si](C)(C)C)cn2C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3nc(CN=[N+]=[N-])cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
(6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol (0.63 g, 1.4 mmol) in DCM (10 mL) was treated with SOCl2 (0.115 mL, 1.58 mmol) and stirred for about 15 min at ambient temperature. The solvents were evaporated then sodium azide (0.280 g, 4.31 mmol) and DMF (5 mL) were added. The mixture was then stirred at ambient temperature overnight. The solvent was evaporated and the residue was partitioned between water (30 mL) and EtOAc (25 mL). The aqueous layer was washed with EtOAc (15 mL) then the combined organic solutions were dried over anhydrous MgSO4, filtered, and concentrated to give 2-(azidomethyl)-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.58 g, 87%): LC/MS (Table 2, Method a) Rt=3.42 min; MS m/z: 464 (M+H)+.
Reaction SMILES: [ClH:1].[F:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[N:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:7]=2[CH:6]=[C:5]([CH3:19])[C:4]=1[F:20].C(N(C(C)C)CC)(C)C.[O:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[ClH:1].[F:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[N:8]([CH:13]3[CH2:14][CH2:15][N:16]([CH:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)[CH2:17][CH2:18]3)[C:7]=2[CH:6]=[C:5]([CH3:19])[C:4]=1[F:20]
Reactant: O=C1CCOCC1
Reactant: Cc1cc2c([nH]c(=O)n2C2CCNCC2)c(F)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2c([nH]c(=O)n2C2CCN(C3CCOCC3)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4,5-Difluoro-6-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride D23 (120 mg) was dissolved in dichloromethane (5 ml) and diisopropylethylamine (0.2 ml, 1.2 mmol), tetrahydro-4H-pyran-4-one (0.2 ml, 2.0 mmol) and sodium triacetoxyborohydride (250 mg, 1.2 mmol) were added and the mixture stirred at room temperature for 4 h. The mixture was partitioned with water/MDC at pH9. Drying (MgSO4), evaporation, and crystallisation of the residue from diethyl ether, washing with dichloromethane gave the title compound free base, which was converted to the hydrochloride. Trituration with diethyl ether gave 35 mg of hydrochloride salt. MH+=352, 1H NMR(HCl salt) (DMSO) □□ 1.7 (2H, m), 2.0 (4H, m), 2.3 (3H, d, J=2 Hz), 2.8 (2H, m), 3.1 (3H, m), 4.0 (2H, bd), 4.5 (1H, m), 7.3 (1H, d, J=5 Hz), 10.3 (1H, bs), and 11.1 (1H, bs); remaining 1H signals not discernible in spectrum
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH3:10].[F:11][C:12]([F:19])([F:18])[C:13](OCC)=[O:14]>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:13](=[O:14])[C:12]([F:19])([F:18])[F:11])=[N:7][C:6]=1[CH3:10]
Reactant: COCCc1scnc1C
Reactant: CCOC(=O)C(F)(F)F
Product: COCCc1sc(C(=O)C(F)(F)F)nc1C

Procedure:
From 5-(2-methoxyethyl)-4-methylthiazole and ethyl trifluoroacetate, following the procedure of Preparation 1. 13C Nmr (CDCl3) 15.2, 27.8, 58.6, 71.3, 116.2 (q, J 288 Hz), 142.2, 154.1, 155.8 and 173.0 (q, J 36 Hz) ppm.
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: NCCOCCO
Product: Nc1nc2nc(SCc3cccc(F)c3F)nc(NCCOCCO)c2s1

Procedure:
Prepared by the method of example 2 step a), using the product of example 4, step b) and 2-(2-aminoethoxy)-ethanol.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][N:46]=[C:47]2[NH2:52]>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].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>[NH2:52][C:47]1[C:48]2[C:43](=[C:42]([C:5]3[N:4]=[C:3]4[C:8]([N:9]=[C:10]([CH2:11][N:12]5[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:16][CH2:17]5)[N:2]4[CH3:1])=[C:7]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:6]=3)[CH:51]=[CH:50][CH:49]=2)[CH:44]=[CH:45][N:46]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Reactant: Nc1nccc2c(Br)cccc12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cccc4c(N)nccc34)nc21
Temperature: 140 °C
Yield: 18.2 %

Procedure:
To a degassed mixture of 2-(1-((9-methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (256 mg, 0.386 mmol), 5-bromoisoquinolin-1-amine (86 mg, 0.386 mmol), copper(I) thiophene-2-carboxylate (74 mg, 0.386 mmol) in 1,4-dioxane (4 mL) was added Pd(PPh3)4 (45 mg, 0.039 mmol). The reaction mixture was heated in the microwave at 140° C. for 35 minutes. The reaction mixture was then loaded onto a Biotage Isolute SPE SCX-2 column The column was first washed with MeOH. The product was eluted with 2 M NH3 in MeOH and concentrated. The crude was further purified by RP-HPLC to give 147 (36.3 mg, 18.2%). LCMS: M+H+=517.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.28 (d, 1H), 8.11 (d, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.53 (t, 1H), 6.80 (s, 2H), 4.23 (s, br, 4H), 4.09 (s, 1H), 3.81 (s, 3H), 3.73 (m, 6H), 2.90 (m, 2H), 2.02 (m, 2H), 1.66 (m, 2H), 1.19 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([Cl:18])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][CH2:23][CH:22]1[C:31](Cl)=[O:32]>CO>[ClH:18].[O:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][CH2:23][CH:22]1[C:31]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([Cl:18])[CH:13]=3)[N:8]=2)[CH2:2][CH2:3]1)=[O:32]
Reactant: O=C(Cl)C1CCc2ccccc2O1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1Cl
Solvent: CO
Product: COc1cc2nc(N3CCN(C(=O)C4CCc5ccccc5O4)CC3)nc(N)c2cc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 0.10 mole of 2-(piperazin-1-yl)-4-amino-6-chloro-7-methoxyquinazoline in 300 ml. of methanol is added with vigorous stirring, 0.10 mole of 2,3-dihydro-4H-benzopyran-2-carboxylic acid chloride. After the addition is complete, the mixture is stirred for three hours at room temperature and the precipitated title compound is collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[CH2:5][Mg]Cl.C(OCC)C.CN(CCN(C)C)C.[Si:25]([O:32][C@H:33]([CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])/[CH:34]=[N:35]/[S@:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C1COCC1>[Si:25]([O:32][C@H:33]([CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[C@@H:34]([NH:35][S@:36]([C:38]([CH3:39])([CH3:40])[CH3:41])=[O:37])[CH2:5][C:4]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]([Cl:1])[CH:3]=1)([C:28]([CH3:31])([CH3:29])[CH3:30])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[S@](=O)/N=C/[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: Fc1cc(Cl)cc(C[Mg]Cl)c1
Agent: CN(C)CCN(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(Cl)c1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A 500 mL RB flask containing (3-chloro-5-fluorobenzyl)magnesium chloride, 0.25 M in diethyl ether (13040 μl, 3260 μmol) was allowed to stir at −78° C. for 5 minutes. At this time, TMEDA (492 μl, 3260 μmol) was added via a syringe and then THF (10 mL) was added via a syringe and the mixture was allowed to stir for 15 min before the addition of (S,E)-N-((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide (550.00 mg, 1304 μmol) (14 mL THF) via a syringe. The reaction was allowed to stir for 30 min and then quenched with ammonium chloride (sat, 100 mL). The aq. layer was extracted with EtOAc (3×100 mL). The combined organics were washed with brine and dried with sodium sulfate. The dried solution was filtered and concentrated to give 1.30 g of a crude oil that was purified on a 120 g ISCO column to give the title compound. Rf=0.40 in 20% EtOAc in hexanes.