Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([N:23](C)[CH3:24])=[O:22])[CH2:16][CH2:15]1.[CH2:26](N)[CH2:27]C>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][C:21]([NH:23][CH2:24][CH2:26][CH3:27])=[O:22])[CH2:18][CH2:19]1
Reactant: CN(C)C(=O)CN1CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Reactant: CCCN
Product: CCCNC(=O)CN1CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1

Procedure:
The title compound was synthesized following the method described for 2-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-acetamide (43), using propylamine. Rt=0.98 min (Method B). Detected mass: 378.2 (M+H+).
Reaction SMILES: N1C=CC=CC=1.Cl.[NH2:8][OH:9].[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]2[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][C:20]=2[C:21]([NH:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:13][CH:12]=1>CO>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]2[CH:33]=[CH:32][C:31](/[CH:34]=[N:8]\[OH:9])=[CH:30][C:20]=2[C:21]([NH:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1)c1cc(/C=N\O)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyridine (0.69 ml, 8.56 mmol) and hydroxylamine hydrochloride (119 mg, 1.71 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-formyl-N-3-pyridinylbenzamide (may be prepared as described in Example 82; 300 mg, 0.86 mmol) in methanol (10 ml) and the mixture was stirred at room temperature for 30 min. The mixture was evaporated under reduced pressure to half volume. The mixture was diluted with water (20 ml) and filtered. The solid was washed with cold water (20 ml)/cold methanol (5 ml) and dried under vacuum to yield the title compound as a white solid. 220 mg.
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1>[I-].[K+]>[OH:3][CH2:2][CH2:1][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: OCCCl
Reactant: O=C(O)c1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Product: O=C(O)c1ccc(OCCO)cc1

Procedure:
That is, as the reaction formula described below, ethylene chlorohydrin and 4-hydroxybenzoic acid are refluxed under heating in an aqueous alkali solution using potassium iodide as a catalyst to obtain 4-(2-hydroxyethoxy)benzoic acid, the product is then reacted with vinyl (meth)acrylate in THF (tetrahydrofuran) having added thereto lipase PS and a small amount of p-methoxyphenol to form 4-(2-propenoyloxyethoxybenzoic acid) (meth)acrylate, and by esterifying the (meth)acrylate thus obtained in methylene chloride with an isosorbide derivative in the presence of DCC (dicyclohexylcarbodiimide) and DMAP (dimethylaminopyridine), the desired product of the formula (b1) can be obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(Br)cc2)C2CCCC2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CC(c1ccc(Br)cc1)C1CCCC1)c1ccc(=O)[nH]c1

Procedure:
In analogy to example 162, step 2, 3-(4-bromo-phenyl)-3-cyclopentyl-1-(6-methoxy-pyridin-3-yl)-propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colorless foam, MS (ESI+): m/z=374.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:9]12[O:16][CH2:15][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]1)[CH2:11][O:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]C#C.C(O)CCCCCC#C>>[CH2:1]([C:9]12[O:10][CH2:11][C:12]([CH2:17][CH2:18][CH3:19])([CH2:15][O:16]1)[CH2:13][O:14]2)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCCCCC12OCC(CCC)(CO1)CO2
Agent: C#CCCCCCCO
Product: C#CCCCCC12OCC(CCC)(CO1)CO2

Procedure:
In an analogous manner the following compound was also prepared: 1-(Oct-7-ynyl)-4-propyl-2,6,7-trioxabicyclo[2.2.2]octane from oct-7-yn-1-ol (ref British patent 969,816, Chem. Abs, 1965, 62, 1571f).
Reaction SMILES: [ClH:1].[C:2]([CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)(=O)[CH3:3].Cl.[CH2:14]([O:16][NH2:17])[CH3:15]>CO>[ClH:1].[CH2:14]([O:16][N:17]=[C:2]([CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)[CH3:3])[CH3:15]
Reactant: CC(=O)C1CN2CCC1CC2
Reactant: CCON
Agent: Cl
Solvent: CO
Product: CCON=C(C)C1CN2CCC1CC2

Procedure:
1.9 g of 3-acetyl quinuclidine hydrochloride and 0.98 g of O-ethylhydroxylamine hydrochloride are heated for 20 minutes to reflux in 30 cm3 of methanol, followed by concentrating to dryness and purifying by chromatography on alumina (eluant: methylene chloride-methanol 9-1). The reaction medium is acidified using gaseous hydrochloric acid, then evaporated to dryness. After crystallizing from ethanol, filtering, and rinsing with ether, 1.3 g of expected product is recovered. M.p.=198°-200° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=O.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1>[CH2:29]([N:36]1[CH2:41][CH2:40][N:39]([C:1]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[CH2:7]3)=[O:3])[CH2:38][CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C1Cc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Reaction time: 5 h
Yield: 17 %

Procedure:
5-Carboxyoxindol (0.93 g), 1.3 g of DCC, and 1.1 g of benzylpiperazine were suspended in 10 ml of dioxane, and the suspension was stirred at 60° to 70° C. for 5 hours. After completion of reaction, the solvent was distilled off and ethyl ether was added to the residue and crystals which precipitated were filtered off. After concentrating the filtrate, the residue was dissolved with an addition of chloroform. The solution was washed with water and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was distilled off. The residue were recrystallized from isopropyl alcohol to give 300 mg of 5-(4-benzyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@@H:18]1[CH2:30]O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@@H:18]1[CH2:30][F:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To an ice cooled solution of DAST (2 equivalents) in methylene chloride under N2 was added the alcohol prepared in Step 4 in methylene chloride dropwise. The yellow solution was stirred at 0° C. to room temperature for 20 hours. The reaction was diluted with NaHCO3, and the organic layer was separated and dried over sodium sulfate. The crude product was chromatographed on silica gel eluting with 10-50% EtOAc/hexanes giving the desired title compound as a yellow oil (40%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc([N+](=O)[O-])cc1)cn2C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(N)cc1)cn2C
Reaction time: 6 h
Yield: 90.9 %

Procedure:
A mixture of 1-methyl-3-(4-nitro-phenylmethyl)-1H-indole-5-carboxylic acid methyl ester (0.23 g, 0.71 mmol), Pd (10% on carbon, 30 mg) and methanol (5 mL) was stirred under a hydrogen atmosphere (ballon) for 6 hr. The catalyst was removed by filtration and the solvents removed in vacuo to provide of 3-(4-amino-benzyl)-1-methyl-1H-indole-5-carboxylic acid methyl ester (0.19 g, 92% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH:15]1[C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20][C:19]=2[C:18](B(O)O)=[CH:17][CH:16]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C.C1(C)C=CC=CC=1>[CH:4]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[C:2]([C:27]2[C:21]3[O:20][C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:23]=4[C:22]=3[CH:24]=[CH:25][CH:26]=2)[CH:3]=1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)[nH]c1ccc(-c3cccc4c3oc3ccccc34)cc12
Temperature: 80 °C
Yield: 85 %

Procedure:
In a 200-mL three-neck flask were put 2.0 g (8.1 mmol) of 3-bromocarbazole, 1.7 g (8.1 mmol) of dibenzofuran-4-boronic acid, and 150 mg (0.5 mol) of tri(ortho-tolyl)phosphine, and the air in the flask was replaced with nitrogen. To this mixture were added 20 mL of toluene, 20 mL of ethanol, and 15 mL (0.2 mol) of an aqueous potassium carbonate solution (2.0 mol/L). In the flask, the mixture was degassed by being stirred under reduced pressure. After 23 mg (0.10 mmol) of palladium(II) acetate was added to this mixture, the mixture was refluxed at 80° C. After the reflux, the mixture was cooled to room temperature, and then the obtained solid was collected by suction filtration. The collected solid was dissolved in 100 mL of toluene, and this solution was filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). The solid obtained by concentration of the obtained filtrate was recrystallized from toluene/hexane, so that 2.3 g of a white solid was obtained in 85% yield. The synthesis scheme of Step 1 is illustrated in (a-2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C@@H:13]([NH:15][C:16]3[N:21]=[C:20]([N:22]4[C@@H:26]([C@@H:27]([OH:29])[CH3:28])[CH2:25][O:24][C:23]4=[O:30])[CH:19]=[CH:18][N:17]=3)[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:40][S:41]([O:29][C@H:27]([C@H:26]1[CH2:25][O:24][C:23](=[O:30])[N:22]1[C:20]1[CH:19]=[CH:18][N:17]=[C:16]([NH:15][C@H:13]([C:10]2[S:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12][CH:11]=2)[CH3:14])[N:21]=1)[CH3:28])(=[O:43])=[O:42]
Reactant: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)O)n1)c1cnc(-c2ccc(Cl)cc2)s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)OS(C)(=O)=O)n1)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a round bottom flask with stir bar was added (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (19 mg, 0.04 mmol) followed by the addition of DCM (1 mL) under nitrogen. Mixture was cooled to 0° C. in a ice/water bath. To this cold solution was added DIEA (0.03 mL, 0.17 mmol) followed by the addition of methanesulfonyl chloride (10 μL, 0.13 mmol). Reaction mixture stirred for 1 hr at 0° C. The reaction mixture was then quenched with water and diluted with DCM. Phases partitioned and the aqueous phase extracted with DCM. Organic layers combined and washed with brine, dried (Na2SO4), filtered and concentrated to afford a orange residue of (S)-1-((R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-2-oxooxazolidin-4-yl)ethyl methanesulfonate (21 mg, 0.04 mmol, 94% yield). LCMS m/z 524.2 (M+H)+, Rt 0.75 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[O:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].Cl[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:31][C:30]1[C:25]([O:1][C:2]2[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=2)[O:7][C:8]2[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=2[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:26][CH:27]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:29]=1
Reactant: COC(=O)COc1ccccc1Oc1cc(O)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1Oc1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 27.2 %

Procedure:
A mixture of methyl [o-(5-hydroxy-2-nitrophenoxy)phenoxy]acetate (1.9 g, 5.9 mmol), 2,3-di-chloro-5-(trifluoromethyl)pyridine (1.92 g, 8.9 mmol) and potassium carbonate (1.23 g, 8.9 mmol) in N,N-di-methylformamide is heated at 100° C. for 12 hours, cooled to room temperature, poured into water and extracted with ether. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a yellow oil. Flash chromatography of the oil using silica gel and a (1:4) ethyl acetate/hexanes solution gives the title product as a yellow liquid (0.8 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH2:21])=[O:20])[CH:14]=1.[C:23](Cl)(=[O:25])[CH3:24]>C(OCC)(=O)C.CCCCCC>[C:23]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH2:21])=[O:20])[CH:14]=1)(=[O:25])[CH3:24]
Reactant: NC(=O)c1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1c(C(=O)c2cccc(C(N)=O)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-2-(3-aminocarbonylbenzoyl)-6-chloroindole (Example 128) and acetyl chloride. m.p.: 243-247° C. (ethyl acetate/hexane)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH:36]=1)[C:28](=[O:35])[C:29]([C:32](O)=[O:33])=[CH:30][N:31]=2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:32]([C:29]2[C:28](=[O:35])[N:27]3[CH:36]=[C:23]([CH3:22])[CH:24]=[CH:25][C:26]3=[N:31][CH:30]=2)=[O:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: COc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Reactant: Cc1ccc2ncc(C(=O)O)c(=O)n2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4cnc5ccc(C)cn5c4=O)cc3F)ccnc2c1
Reaction time: 16 h
Yield: 22.7 %

Procedure:
To a suspension of ethyl 7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (0.11 g, 0.47 mmol) in ethanol was added 1 N NaOH solution (3 mL, 3 mmol) at RT. The reaction mixture was stirred for 16 at RT. The resultant was concentrated, and the residue was diluted with water. The aqueous solution was washed with diethyl ether and then acidified with 2N HCl solution and extracted with dichloromethane. The organic solution was dried over magnesium sulfate and concentrated to give a yellow solid (0.090 g, 93%): MS (ESI pos. ion) m/z: 205 (MH+). Calc'd exact mass for C10H8N2O3: 204. A mixture of 3-fluoro-4-(7-methoxyquinolin-4-yloxy)benzenamine (0.08 g, 0.3 mmol), 7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (0.08 g, 0.4 mmol), HATU (0.4 g, 0.8 mmol) in dichlormethane was stirred for 16 h. Then, the mixture was diluted with dichloromethane and aq. NaHCO3 solution. The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified by ISCO (0-5% MeOH in EtOAc) to give the title compound as a yellow solid (0.032 g, 24%): MS (ESI pos. ion) m/z: 471 (MH+), Calc'd exact mass for C26H19FN4O4: 470; 1HNMR (400 MHz, CDCl3): 11.4 (s, 1H), 9.4 (s, 1H), 9.1 (s, 1H), 8.6 (d, J=6 Hz, 1H), 8.3 (d, J=9 Hz, 1H), 8.0 (dd, J=3, 12 Hz, 1H), 7.9 (m, 2H), 7.5 (m, 1H), 7.4 (d, J=3 Hz, 1H), 7.0-7.3 (m, 2H), 6.4 (d, J=3 Hz, 1H), 3.98 (s, 3H), 2.57 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:37][CH:38]2[CH:43]3[CH2:44][CH2:45][CH:40]([CH2:41][CH2:42]3)[CH:39]2[C:46]([O:48][CH3:49])=[O:47])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[N:6][CH:7]=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:37][CH:38]2[CH:43]3[CH2:42][CH2:41][CH:40]([CH2:45][CH2:44]3)[CH:39]2[C:46]([O:48][CH3:49])=[O:47])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][N:9]=2)=[N:6][CH:7]=1
Reactant: COC(=O)C1C2CCC(CC2)C1Nc1nc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)ncc1Cl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1C2CCC(CC2)C1Nc1nc(-c2n[nH]c3ncc(F)cc23)ncc1Cl
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of (+/−)-trans-(2,3)-methyl 3-((5-chloro-2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate, 38, (0.85 g, 1.26 mmol) in CH2Cl2 (42.5 mL) at room temperature was added Et3SiH (1.00 mL, 6.32 mmol) followed by trifluoroacetic acid (0.97 mL, 12.60 mmol). The reaction was stirred at room temperature. After the reaction was complete, as judged by LC-MS, the solution was concentrated in vacuo. Careful flash chromatography (SiO2, 0-7% MeOH—CH2Cl2, gradient elution) provided the desired product (373 mg, 66% yield)L 1H NMR (400 MHz, MeOD) δ 8.66 (dd, J=8.3, 2.5 Hz, 1H), 8.53 (s, 1H), 8.28 (s, 1H), 5.05 (d, J=6.5 Hz, 1H), 3.69 (s, 3H), 2.95 (d, J=6.8 Hz, 1H), 2.09 (s, 1H), 1.98 (s, 1H), 1.96-1.79 (m, 3H), 1.77-1.61 (m, 3H), 1.61-1.45 (m, 2H); LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=2.55 min, (M+H) 431.14.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([N:8]2[CH2:12][CH2:11][CH:10]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:9]2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(S(=O)(=O)c3ccc(O)cc3)C2)CC1

Procedure:
The title compound, MS: m/e=411.3 (M+H+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester following the procedure described for example 1.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].S(Cl)(Cl)=O.[CH3:17]N.[Cl-].[Na+]>CO>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:17])=[O:11])(=[O:3])[CH3:2]
Reactant: CN
Reactant: CC(=O)NCCCCCC(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)CCCCCNC(C)=O
Temperature: 25 °C

Procedure:
Methyl 6-acetamidohexanoate was prepared as a low-melting solid by sequential treatment of 6-acetamido hexanoic acid with thionyl chloride and methanol. Five grams of this compound, (27 mmol) was dissolved in an excess of 40% aqueous methylamine solution, and the resulting mixture was stirred for sixteen hours at room temperature. The reaction mixture was saturated with sodium chloride and extracted several times with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was removed in vauo to yield a crude residue. Recrystallization from THF yielded 4.5 grams (90%) of pure product, melting point 99°-100° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20]CC2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C(=Cc1ccccc1OCc1ccccc1)CCCCCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccccc1CCCCCCCc1ccccc1
Yield: 69 %

Procedure:
The whole of this benzyl 2-(7-phenyl-1-heptenyl)phenyl ether was then treated with hydrogen in the presence of 200 mg of 5% w/w palladium-on-carbon in 250 ml of ethanol at 50° C. for 5 hours at atmospheric pressure. At the end of this time, insoluble materials were removed by filtration, and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.03 g (yield 69%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]([NH:12]C(=O)OC(C)(C)C)[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])#[N:2].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[C:20]1([CH3:30])[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[NH2:12][CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6]
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)NCC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)CC(N)C(=O)NCC#N
Reaction time: 12 h

Procedure:
A mixture comprised of the tert-butyl 1-cyanomethylcarbamoyl-3-methylbutylcarbamate and anhydrous p-toluenesulfonic acid (3 eq.) in methylene chloride (20 mL) was stirred for approximately 12 hours. The mixture was filtered and the solid material collected was triturated several times with ether to remove excess acid and then dried under vacuum to provide 2-amino-N-cyanomethyl-4-methylpentanamide p-toluenesulfonic acid salt.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2)[N:3]=1.[S:24]1[C:28]([NH2:29])=[N:27][CH:26]=[N:25]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:24]1[C:28]([NH:29][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=3)[N:3]=2)=[N:27][CH:26]=[N:25]1
Reactant: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1
Reactant: Nc1ncns1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Cl)cc(Nc3ncns3)n2)cc1
Yield: 31.6 %

Procedure:
To a round bottom flask was added N-(4-(4,6-dichloropyrimidin-2-ylthio)phenyl)-3,3,3-trifluoropropanamide (350 mg, 0.9 mmol), 1,2,4-thiadiazole-5-amine (100 mg, 0.9 mmol), xanthphos (50 mg, 0.1 mmol), Pd2 dba3 (50 mg, 0.05 mmol), NaCO3 (150 mg, 1.5 mmol) and dioxane(10 cm). The mixture was flushed with nitrogen and then brought to reflux for 2 hours. The mixture was filtered, partitioned between ethylacetate and bicarbonate. The organic layer was dried with magnesium sulfate, and concentrated to an oil, which was purified by column chromatography to yield the product as a yellow solid (127 mg, 34%)