Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][CH:12]([F:27])[C:13]1[N:18]=[CH:17][C:16]([CH:19]([CH2:22][C:23]2([F:26])[CH2:25][CH2:24]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH:12]([F:27])[F:11])=[N:14][CH:15]=1)[CH2:22][C:23]1([F:26])[CH2:25][CH2:24]1)=[O:6]
Reactant: NCC(CC1(F)CC1)c1cnc(C(F)F)nc1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(CC1(F)CC1)c1cnc(C(F)F)nc1)c1ccccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=384.1, tR (minutes, Method F)=2.72. [α]D20=+21.30 (c=2.39 mg/mL,CHCl3)
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][N:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.P(Br)(Br)[Br:15].C1COCC1.C([O-])(O)=O.[Na+]>C(OCC)C.C(OCC)(=O)C>[Br:15][CH2:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:11]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccnc(-n2cccn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: BrCc1ccnc(-n2cccn2)c1
Temperature: 65 °C
Yield: 69.3 %

Procedure:
To a stirred solution of (2-(1H-pyrazol-1-yl)pyridin-4-yl)methanol (175 mg, 1.00 mmol) in diethyl ether (5 mL), PBr3 (0.11 mL, 1.00 mmol) was added dropwise at 0° C. Then THF (5 mL) was added to the resulting white precipitate and the mixture was heated at 65° C. for 1 h. The mixture was cooled to rt, diluted with ethyl acetate (5 mL) and poured into saturated aqueous NaHCO3 solution (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield the title compound (165 mg, 70%). [LCMS RtE=1.33 min, [M+H]+=237.9/239.9].
Reaction SMILES: [S:1]=[CH:2][NH:3][CH:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5]([O:7]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[S:1]=[CH:2][NH:3][CH:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C(NC=S)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)C(NC=S)c1ccccc1

Procedure:
3.61 g. (0.01 mol.) of α-[(thioxomethyl)amino]-benzeneacetic acid, diphenylmethyl ester are added to a mixture of 30 ml. of trifluoroacetic acid and 5 ml. of anisole at 0°-5° and the mixture is stirred for ten minutes. The mixture is concentrated, sodium bicarbonate solution is added to the residue and the aqueous phase is extracted with ether. This is then layered over with fresh ether, acidified and the aqueous phase is extracted twice with ether. Concentration of the ether solution yields α-[(thioxomethyl)amino]benzeneacetic acid as an oily residue.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][OH:6].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:8])([F:7])[F:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCC(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.4 %

Procedure:
To a solution of 4,4,4-trifluorobutan-1-ol (5.0 g, 39.0 mmol) in CH2Cl2 (30 mL) and pyridine (20 mL) was added 4-(dimethylamino)pyridine (0.24 g, 2.0 mmol) followed by p-toluenesulfonyl chloride (7.4 g, 39.0 mmol). The mixture was allowed to stir at ambient temperature for 20 hours then was quenched with 5% aqueous HCl (20 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×5 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (5.0 g, 17.7 mmol, 45% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.86-1.98 (m, 2H) 2.06-2.24 (m, 2H) 2.46 (s, 3H) 4.09 (t, J=5.9 Hz, 2H) 7.37 (d, J=7.8 Hz, 2H) 7.79 (d, J=8.5 Hz, 2H).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20](=O)[C:21]([CH3:24])([CH3:23])[CH3:22])(=O)OC.O.[NH2:27][NH2:28]>>[C:21]([C:20]1[CH:19]=[C:4]2[C:3]([C@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]2[CH2:6][CH2:7]3)=[N:28][N:27]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: COP(=O)(CC(=O)C(C)(C)C)OC
Reactant: NN
Solvent: O
Product: CC(C)(C)c1cc2c(nn1)[C@@]1(C)CC[C@@H]2C1(C)C

Procedure:
MS (EI): 244.3 (M+), light-yellow crystalline solid. Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, (3,3-dimethyl-2-oxo-butyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.[CH:19]([Li])(CC)C.[Cl-].[NH4+].O.[O:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[C:11]([O:10][C:9](=[O:15])[NH:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:17][CH3:18])=[CH:4][C:5]=1[CH2:16][CH:31]([OH:27])[CH:30]([CH3:19])[CH2:29][CH3:28])([CH3:12])([CH3:13])[CH3:14]
Reactant: COc1cc(C)c(NC(=O)OC(C)(C)C)cc1Cl
Reactant: [Li]C(C)CC
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CCC(C)C(O)Cc1cc(OC)c(Cl)cc1NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, to a solution of tert-butyl (5-chloro-4-methoxy-2-methylphenyl)carbamate (1.00 g) in tetrahydrofuran (18.4 mL) was added dropwise sec-butyllithium (1.08 mol/L hexane-cyclohexane solution, 7.5 mL) at −45° C., and the mixture was stirred for 30 minutes. Next, a solution of 2-methylbutyl aldehyde (0.430 mL) in tetrahydrofuran (1.84 mL) was added dropwise thereto, and the mixture was stirred at −45° C. for 35 minutes and then stirred at room temperature for 90 more minutes. To the reaction mixture was added saturated aqueous ammonium chloride solution/water (3/1, 40 mL), followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (876 mg). 1H-NMR (CDCl3) δ ppm: 0.50-2.30 (19H, m), 2.45-2.95 (2H, m), 3.55-4.05 (4H, m), 6.60-6.80 (1H, m), 7.20-8.00 (2H, m).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]1([CH2:7][CH2:8][N:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:18]([CH3:17])(=[O:20])=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CCNCc2cccnc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(CCc1ccccc1)Cc1cccnc1

Procedure:
A 4.4 g. portion of 3-(2-phenylethyl)aminomethylpyridine was reacted with 2.4 g. of methanesulfonyl chloride in the presence of 4 g. of potassium carbonate in 60 ml. of dichloromethane at ambient temperature for several days. The mixture was then diluted with 100 ml. of dichloromethane and extracted with 50 ml. of water. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The residue was taken up in toluene and chromatographed on silica gel, eluting with 9:1 toluene:acetone. The product-containing fractions were combined and evaporated under vacuum, and the residue solidified on standing. The solids were triturated in ether and dried to obtain 1.8 g. of the desired product, m.p. 94°-95°.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[C:25][C:26]4[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[C:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[O:31])=[CH:28][CH:27]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C1COCCN1
Reactant: COCCOCOc1ccc(C#Cc2ccc(C(=O)Cl)cc2)cc1C12CC3CC(CC(C3)C1)C2
Product: COCCOCOc1ccc(C#Cc2ccc(C(=O)N3CCOCC3)cc2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 76.3 %

Procedure:
In a manner analogous to Example 25(b), by reaction of 1.1 g (2.3 mmol) of 4-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl]benzoyl chloride with 600 μl (6.8 mmol) of morpholine, 930 mg (44%) of the expected amide were obtained, which amide had the melting point 142°-3° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6]2[CH:7]=[CH:8][C:9]([C:11](OC)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1.[BH4-].[Li+].CO.O>O1CCCC1>[CH3:1][C:2]1([CH3:15])[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)OCC2(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)COc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
To a solution of methyl 3,3-dimethyl-2,3-dihydro-1-benzofuran-6-carboxylate (44 mg, 0.21 mmol) prepared in the method of US2009/105209 in tetrahydrofuran (1.5 mL) were added lithium borohydride (23 mg, 1.07 mmol) and methanol (43 μL, 1.07 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added water, and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give the title compound (38 mg, 100%) as a colorless and clear oil.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:3]/[C:4]([O:6][C@@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:10][C@@:9]([O:33]C)([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[N:19]2CC2C=CC(OC)=CC=2)[CH2:8]1)=[O:5].CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[CH3:1]/[C:2](/[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:3]/[C:4]([O:6][C@@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:10][C@@:9]([OH:33])([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[NH:19]2)[CH2:8]1)=[O:5]
Reactant: CCCCC[C@@H]1C[C@@H](OC(=O)/C=C(/C)CCCC)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: CCCCC[C@@H]1C[C@@H](OC(=O)/C=C(/C)CCCC)C[C@](O)([C@@H]2CSC(=O)N2)O1

Procedure:
Application of the method shown in Example 46, with the modification that (Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-pentyl-tetrahydro-2H-pyran-4-yl) 3-methylhept-2-enoate is substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[F:26][C:27]([F:33])([F:32])[CH2:28][C:29](=O)[CH3:30].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:29]([CH2:28][C:27]([F:33])([F:32])[F:26])[CH3:30])[CH2:24][CH2:25]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Reactant: CC(=O)CC(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(CC(F)(F)F)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 70 °C

Procedure:
A solution of 5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 60 (0.37 g, 1 mmol) in 11 mL of 95:5 methanol-acetic acid was treated with excess of 4,4,4-trifluorobutan-2-one (1 g, 7.9 mmol), followed by sodium cyanoborohydride (0.25 g, 4 mmol). The reaction mixture was heated at 70° C. overnight, after which a small trace of the desired product was detected by LC-MS analysis. The crude reaction mixture was directly submitted to silica gel chromatography; elution with 9:1 dichloromethane-2 M ammonia in methanol provided a small amount of impure product. Further purification by preparative thin layer chromatography afforded 10 mg of the title compound, identified by LC-MS (Method A).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[S:14])[N:12]([CH2:15]O)[C:11](=[S:17])[O:10]2)=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[S:14])[N:12]([CH2:15][Cl:20])[C:11](=[S:17])[O:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(-n2oc(=S)n(CO)c2=S)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-n2oc(=S)n(CCl)c2=S)cc1

Procedure:
2-(4-Cyanophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dithione (0.03 mole) dissolved in chloroform (40 ml) and thionyl chloride (0.06 mole) dissolved in chloroform (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is stripped of solvent under reduced pressure, leaving a residue. This residue is dissolved in toluene, and the toluene solution is stripped of solvent and unreacted starting materials to yield the desired product 2-(4-cyanophenyl)-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dithione as the residue.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[I-:18].[Na+].C(OC)(C)(C)C>CC(C)=O>[I:18][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: [I-]
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: Cc1oc(-c2ccc(C(C)C)cc2)nc1CI

Procedure:
1.74 g of 4-Chloromethyl-5-methyl-2-(4-(2-propyl)-phenyl)-oxazole and 3 g of sodium iodide in 150 ml of acetone are heated under reflux for 2 hours. After the reaction mixture has been cooled, 300 ml of methyl tert-butyl ether are added, the mixture is washed three times with saturated Na2S2O3 solution and dried over MgSO4 and the solvents are then removed under reduced pressure. This gives 2.64 g of 4-iodomethyl-5-methyl-2-(4-(2-propyl)-phenyl)-oxazole as a yellowish solid. C14H16INO (341.19), MS(ESI): 342 (M+H+).
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:19][C:20]([C:22]1([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl.C(O)=O>[NH2:28][C:22]1([C:20]([NH:19][C@H:3]([C:2]#[N:1])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[CH:9][CH:10]=2)=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: COc1cc(-c2ccc(C[C@H](NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C(N)=O)cc2)ccn1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Solvent: O=CO
Product: COc1cc(-c2ccc(C[C@@H](C#N)NC(=O)C3(N)CCOCC3)cc2)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.2 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-(2-methoxypyridin-4-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 26, step (i), 214 mg) in dichloromethane (10 mL) was treated with Burgess' reagent (205 mg) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated to give a residue that was dissolved in formic acid (2 mL) which was heated at 50° C. for 15 min. The mixture was evaporated and then methanol was added and the solvent was evaporated. The product was purified by reversed phase HPLC using methanol in 0.1% aqueous TFA as eluent. The residue was converted to the free base by elution through a PL-HCO3 MP cartridge in dichloromethane/methanol to afford the titled compound (95 mg).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[S:11][C:12]3[N:13]=[CH:14][N:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[C:22]([O:26][C:27](=[O:34])[NH:28][C@@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[C:22]([O:26][C:27](=[O:34])[NH:28][C@@H:29]1[CH2:33][CH2:32][N:31]([C:8](=[O:21])[NH:9][C:10]2[S:11][C:12]3[N:13]=[CH:14][N:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)[CH2:30]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: COc1ncnc2sc(NC(=O)Oc3ccccc3)nc12
Solvent: CC#N
Product: COc1ncnc2sc(NC(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc12
Temperature: 25 °C
Yield: 103 %

Procedure:
A solution of (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-carbamic acid phenyl ester (1.5 g, 0.0049 mol) in acetonitrile (80 mL) at 25° C. was treated with pyrrolidin-3(R)-yl-carbamic acid tert-butyl ester (0.92 g, 0.049 mol). The reaction mixture was heated at reflux for 1 h. It was then cooled to 25° C. and concentrated in vacuo. The residue was triturated with ether, filtered and dried in vacuo to afford [1-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-ylcarbamoyl)-pyrrolidin-3(R)-yl]-carbamic acid tert-butyl ester (1.99 g, 99%); LRMS for C16H22N6O4S (M+H) at m/z 395.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][C:12](O)=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][C:16]1[C:17](=[O:36])[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:19](=[O:27])[N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[C:21]=1[NH2:22].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:23]([N:20]1[C:21]2[N:22]=[C:12]([CH2:11][C:8]3[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:10][CH:9]=3)[NH:15][C:16]=2[C:17](=[O:36])[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:19]1=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCn1c(N)c(N)c(=O)n(Cc2ccccc2F)c1=O
Reactant: CC(=O)Nc1ccc(CC(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(C)=O)nc3)nc21

Procedure:
This compound was prepared by the method similar to that described in example 11 (method 1) except that the hydrochloride salt of (6-acetylamino-pyridin-3-yl)-acetic acid was used in place of N-acetyl-4-aminophenylacetic acid and the coupling to 5,6-diamino-1-butyl-3-(2-fluorobenzyl)-1H-pyrimidine-2,4-dione was performed with O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate and diisopropylethyl amine in N,N-dimethylformamide. MS, m/z(M+)=464.1971.
Reaction SMILES: C1(N2C=NC3C2=NC(OCC)=NC=3N)CCCC=C1.[CH:20]1([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][C:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[N:30][C:31]=3[NH2:35])[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1>>[CH2:37]([O:36][C:29]1[N:28]=[C:27]2[C:32]([N:33]=[CH:34][N:26]2[CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:31]([NH2:35])[N:30]=1)[CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Agent: CCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Product: CCCCCOc1nc(N)c2ncn(C3CCCCC3)c2n1
Yield: 90 %

Procedure:
The procedure of Example 8 was repeated except that the 9-(2-cyclohexenyl)-2-ethoxy-9H-adenine used therein was replaced by an equivalent weight of 9-(2-cyclohexenyl)-2-n-pentyloxy-9H-adenine. There was produced the title product in 90% yield; m.p. 64°-68° C. IR(neat): 3500, 3320, 1635, 1590, 1460, 1395, 1340, 1325, 1265 cm-1. UV: λmaxEtOH 253 nm(ε 10900), 269 nm(ε 16800). NMR(CDCl3): 1.50(19H, m), 4.20(1H, m), 4.26(2H, t, J=6.5 Hz), 6.25(2H, s), 7.56(1H, s).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[C:22]([O:28][CH3:29])[CH:21]=1.C[O-].[Na+].Cl>CO.O>[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:15]/[C:14](=[O:16])[C:13]2[C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:22]([O:28][CH3:29])[CH:21]=1
Reactant: COC(=O)c1ccc(C=O)c(OC)c1
Reactant: CC(=O)c1cccnc1Nc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(/C=C/C(=O)c2cccnc2Nc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.8 %

Procedure:
A mixture of 1-(2-phenylamino-pyridin-3-yl)-ethanone (833 mg, 3.92 mmol) in methanol (16.5 mL) at 25° C. was treated with 4-formyl-3-methoxy-benzoic acid methyl ester (508 mg, 2.61 mmol) and sodium methoxide in methanol (4.37M, 1.2 mL, 5.23 mmol). The reaction was stirred at 25° C. for 48 h. At this time, the reaction was diluted with water (100 mL), neutralized with a 1N aqueous hydrochloric acid solution, and extracted with methylene chloride (3×75 mL). The combined organics were dried over sodium sulfate filtered and concentrated in vacuo. Flash chromatography (40 g silica column, 10-50% ethyl acetate/hexanes) afforded 3-methoxy-4-[(E)-3-oxo-3-(2-phenylamino-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (880 mg, 86.8%) as a red solid. ES+-HRMS m/e calcd for C23H20N2O4 [M+H+] 389.1496. Found 389.1494.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C:52]2[N:57]=[CH:56]C(N)=C[CH:53]=2)[CH2:48][CH2:47]1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:56]=[N:57][C:52]([N:49]5[CH2:48][CH2:47][N:46]([CH3:45])[CH2:51][CH2:50]5)=[CH:53][CH:30]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(N5CCN(C)CC5)nc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 6-(4-methylpiperazino)-3-pyridinamine as the aniline component. (37%, MS=569.3 (M+H))
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([CH3:15])[N:9]=2)=[N:3]1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]2[C:13]([O:14][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=[C:10]([CH3:15])[N:9]=2)=[N:3]1
Reactant: Cc1ccc(O)c(-c2cc(C)n(C)n2)n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cc(C)n(C)n3)c2cc1OC
Temperature: 160 °C
Reaction time: 48 h
Yield: 4.2 %

Procedure:
2-(1,5-Dimethyl-1H-pyrazol-3-yl)-6-methyl-pyridin-3-ol (111 mg), 4-chloro-6,7-dimethoxyquinoline (218 mg), and 4-dimethylaminopyridine (130 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 2 days. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (9 mg, yield 4%).