Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([O:12][CH2:13][C:14]([CH3:16])=[CH2:15])[C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:18][C:19]([CH3:21])=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([O:12][CH2:13][C:14]([CH3:16])=[CH2:15])[C:3]=1[C:4]([O:6][CH2:20][C:19]([CH3:21])=[CH2:18])=[O:5]
Reactant: C=C(C)CCl
Reactant: C=C(C)COc1ccc(F)c(F)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COC(=O)c1c(OCC(=C)C)ccc(F)c1F
Temperature: 65 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of 2,3-difluoro-6-(2-methylallyloxy)benzoic acid (732) (1.45 g, 6.35 mmol), 3-chloro-2-methylpropene (0.77 mL, 7.62 mmol), and potassium carbonate (1.76 g, 12.7 mmol) in anhydrous DMF was stirred at 65° C. under N2 overnight. The mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by flash column chromatography eluting with hexanes-EtOAc (4:1) to provide 2-methylallyl 2,3-difluoro-6-(2-methylallyloxy)benzoate (733) (1.55 g, 87%). 1H NMR (400 MHz, CDCl3) δ 7.14 (q, J=9.5 Hz, 1H), 6.63-6.60 (m, 1H), 5.09 (s, 1H), 5.06 (s, 1H), 4.98 (s, 2H), 4.78 (s, 2H), 4.45 (s, 2H), 1.81 (s, 3H), 1.79 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[N:10][C:11]([OH:14])=[N:12][CH:13]=2)=[CH:5][CH:4]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[N:10][C:11]([O:14][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: COc1ccc(Oc2cnc(O)nc2)cc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2cnc(OC(=O)N(C)c3ccccc3)nc2)cc1
Yield: 78.3 %

Procedure:
A solution of 5-(4-methoxy-phenoxy)-pyrimidin-2-ol (0.44 g, 2.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.34 g, 2.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.22 g, 2.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.55 g, 79% yield) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8](CC#N)[C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1.[C:17]([OH:20])(=[O:19])[CH3:18].S(=O)(=O)(O)O.O1CCOCC1>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH2:18][C:17]([OH:20])=[O:19])[C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)O
Reactant: COc1ccc2cc(CC#N)c(C)nc2c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2cc(CC(=O)O)c(C)nc2c1

Procedure:
Compounds of formula (50), wherein R4 and R5 are as defined in formula (I) and R6 is aryl or heteroaryl, can be prepared as described in Scheme 6. Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can be prepared using the procedures described in Synthetic Comm., 17(14):1647-1653 (1987). Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can be treated with a reducing agent, such as, but not limited to, lithium aluminum hydride or sodium borohydride, to provide (7-methoxy-2-methyl-3-quinolinyl)methanol. (7-Methoxy-2-methyl-3-quinolinyl)methanol can be treated with a chlorinating reagent, such as, but not limited to, thionyl chloride to provide 3-(chloromethyl)-7-methoxy-2-methylquinoline. 3-(Chloromethyl)-7-methoxy-2-methylquinoline can be treated with sodium cyanide or potassium cyanide to provide (7-methoxy-2-methyl-3-quinolinyl)acetonitrile. (7-Methoxy-2-methyl-3-quinolinyl)acetonitrile can be treated with acid, such as, but not limited to, glacial acetic acid and concentrated sulfuric acid, in water and 1,4-dioxane with heat to provide (7-methoxy-2-methyl-3-quinolinyl)acetic acid. (7-Methoxy-2-methyl-3-quinolinyl)acetic acid can be treated with a reducing agent, such as, but not limited to, B2H6, borane-THF complex, or borane-pyridine complex, to provide 2-(7-methoxy-2-methyl-3-quinolinyl)ethanol. 2-(7-Methoxy-2-methyl-3-quinolinyl)ethanol can be treated with methanesulfonyl chloride and a base, such as, but not limited to, triethylamine or diisopropylamine to provide 2-(7-methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate. 2-(7-Methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate can be treated with an amine of formula (5) to provide amines of formula (47). Amines of formula (47) can be treated with BBr3 to provide hydroxy compounds of formula (48). Hydroxy compounds of formula (48) can be treated with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride to provide triflates of formula (49). Triflates of formula (49) can be treated with boronic acids of formula (7) as described in Scheme 1 to provide compounds of formula (50).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH2:13][CH2:14][CH2:15][OH:16]>>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:13][CH2:14][CH2:15][OH:16])=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: NCCO
Product: O=[N+]([O-])c1ccc(CCNCCO)cc1
Temperature: 150 °C

Procedure:
A mixture of 1-(2-bromo-ethyl)-4-nitro-benzene (86.9 mmoles) and 2-amino-ethanol (869 mmoles) is heated at 150° C. under microwave activation for 10 minutes. The reaction mixture is evaporated to dryness and the residue obtained is purified on silica gel (SiO2; gradient DCM/MeOH) to yield the title product, which is used directly in the next Step.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Br:12]Br.C([O-])(O)=O.[Na+]>CC(O)=O.C(Cl)(Cl)Cl>[Br:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[NH:2][CH3:1].[Br:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[NH:2][CH3:1]
Reactant: BrBr
Reactant: CNc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CNc1ccc([N+](=O)[O-])cc1Br
Temperature: 10 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of methyl-(4-nitro-phenyl)-amine (15.2 g, 0.1 mol) in AcOH (150 mL) and CHCl3 (50 mL) was added Br2 (16.0 g, 0.1 mol) dropwise at 5° C. The mixture was stirred at 10° C. for 1 h and then basified with sat. aq. NaHCO3. The resulting mixture was extracted with EtOAc (100 mL×3), and the combined organics were dried over anhydrous Na2SO4 and evaporated under vacuum to give (2-bromo-4-nitro-phenyl)-methyl-amine (2-bromo-4-nitro-phenyl)-methyl-amine (23.0 g, 99%), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.37 (d, J=2.4 Hz, 1H), 8.13 (dd, J=2.4, 9.0 Hz, 1H), 6.58 (d, J=9.0 Hz, 1H), 5.17 (brs, 1H), 3.01 (d, J=5.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2](=[O:8])[CH2:3][CH2:4][C:5](O)=[O:6].[NH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[C:40]3[C:35](=[C:36]([Cl:42])[CH:37]=[C:38]([Cl:41])[CH:39]=3)[CH2:34][N:33]([CH3:43])[CH2:32]2)[CH:26]=1)(=[O:24])=[O:23]>>[Cl:41][C:38]1[CH:39]=[C:40]2[C:35](=[C:36]([Cl:42])[CH:37]=1)[CH2:34][N:33]([CH3:43])[CH2:32][CH:31]2[C:27]1[CH:26]=[C:25]([S:22]([NH:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][NH:9][C:5](=[O:6])[CH2:4][CH2:3][C:2]([NH2:1])=[O:8])(=[O:23])=[O:24])[CH:30]=[CH:29][CH:28]=1
Reactant: NC(=O)CCC(=O)O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)CCC(N)=O)c2)C1
Yield: 66.7 %

Procedure:
Compound 247 was prepared following the procedure outlined in Example 215 using 4-amino-4-oxobutanoic acid (7.6 mg, 0.0646 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 28, 50 mg, 0.0646 mmol). Purification by preparative HPLC gave the title compound (27.8 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.88 (d, 1H), 7.75 (s, 1H), 7.64 (t, 1H), 7.55 (s, 1H), 7.51 (d, 1H), 6.84 (s, 1H), 4.78-4.71 (m, 2H), 4.55-4.48 (m, 1H), 3.81-3.75 (m, 1H), 3.63-3.55 (m, 10H), 3.51-4.45 (m, 5H), 3.44-3.41 (m, 3H), 3.38-3.31 (m, 3H), 3.13 (s, 3H), 3.07-3.02 (t, 2H), 2.48-2.43 (m, 4H). MS (m/z): 645.32 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:28][C@H:27]([OH:29])[CH2:26][C@H:25]4[C:30](O)=[O:31])[C:17]4[S:22](=[O:23])[CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([N:36](C(C)C)CC)(C)C.N.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:28][C@H:27]([OH:29])[CH2:26][C@H:25]4[C:30]([NH2:36])=[O:31])[C:17]4[S:22](=[O:23])[CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1C[C@@H](O)CN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
80 mg (2S,4R)-1-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl}-4-hydroxy-pyrrolidine-2-carboxylic acid are placed in 2.00 ml N,N-dimethylformamide and combined with 86.77 mg diisopropylethylamine and 76.20 mg O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluronium-hexafluoro-phosphate (HATU). The mixture is stirred for 0.25 hours at ambient temperature, then 334 μl ammonia solution (0.5 M in dioxane) are added. The reaction mixture is stirred for 3 hours at ambient temperature, then acidified and water is added. The diastereomers are separated by preparative HPLC (method B). 11.7 mg of Diastereomer 1 and 15.3 mg of Diastereomer 2 (Example 128) are obtained as powders. Analytical HPLC-MS (method A): Diastereomer 1, RT=1.49 min, Diastereomer 2, RT=1.49 min.
Reaction SMILES: [OH:1][C:2]1[C:23]2[C:22](=[O:24])[C:9]3[O:10][C:11](=[O:21])[C:12]4[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([O:19]C)[C:13]=4[C:8]=3[C:7](=[O:25])[C:6]=2[CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:19][C:14]1[C:13]2[C:8]3[C:7](=[O:25])[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([OH:1])[C:23]=4[C:22](=[O:24])[C:9]=3[O:10][C:11](=[O:21])[C:12]=2[CH:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: COc1cc(C)cc2c(=O)oc3c(c12)C(=O)c1cccc(O)c1C3=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)c2c3c(oc(=O)c2c1)C(=O)c1c(O)cccc1C3=O
Reaction time: 2 h
Yield: 57.4 %

Procedure:
In methylene chloride was dissolved 8-hydroxy-1-methoxy-3-methyl-7,12-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-5,7,12-trione (2 g), and under ice-cooling, a methylene chloride solution of boron tribromide (2 ml) was added dropwise. The mixture was further stirred at that temperature for 2 hours, at the end of which time it was washed with water and dried over magnesium sulfate. The solvent was then distilled off to give crude crystals. Recrystallization from methanol gave yellow crystals (1.1 g). m.p. 236°-238° C.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH2:15].C(N(CC)CC)C>CN1C(=O)CCC1>[F:8][C:7]1[C:2]([NH:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([F:10])[CH:12]=2)=[N:3][C:4]([F:9])=[CH:5][CH:6]=1
Reactant: NCc1cccc(F)c1
Reactant: Fc1ccc(F)c(F)n1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Fc1cccc(CNc2nc(F)ccc2F)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
2,3,6-trifluoropyridine (1.07 mL, 1.5 g, 11.27 mmol), 3-fluorobenzylamine (3.18 mL, 3.53 g, 28.2 mmol), and triethylamine (4.71 mL, 3.42 g, 33.8 mmol) were dissolved in NMP (39 mL) to form a mixture This mixture reaction mixture was stirred at 100° C. for 1 hr. The reaction mixture was then extracted with EtOAc (3×75 mL). The combined extracts were washed with H2O (4×75 mL) followed by brine (1×75 mL). The organic layer was dried (Na2SO4), filtered, and the solvent removed in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 100 hexanes to 30 EtOAc/70 hexanes yielded 2.63 g (98%) of 3,6-difluoro-N-(3-fluorobenzyl)pyridine-2-amine. LCMS (m/z): 239.1 (MH+), retention time=1.01 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: COc1ccc2c(-c3ccc(C(C)(C)C)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-tert-butyl-phenylboronic acid to give [1-(4-tert-butyl-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 387(MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.CC1C=CC(S(O[CH2:23][CH:24]2[CH2:28][O:27][C:26](=[O:29])[NH:25]2)(=O)=O)=CC=1>C(#N)C>[N:7]1([CH2:23][CH:24]2[CH2:28][O:27][C:26](=[O:29])[NH:25]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(=O)N2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1NC(CN2CCCC2)CO1
Yield: 92 %

Procedure:
Potassium carbonate (0.62 g, 4.5 mmol, 2 eq) and pyrrolidine (0.28 ml, 3.37 mmol, 1.5 eq) are added to a solution of (2-oxo-1,3-oxazolidin-4-yl)methyl 4-methylbenzenesulfonate a91 (0.62 g, 2.25 mmol, 1 eq) in acetonitrile (22 ml). The mixture is heated at reflux overnight. After cooling, the mixture is filtered and the solid is washed with acetonitrile. The acetonitrile phases are concentrated in vacuo. The residue is taken up in dichloromethane, heated, filtered and washed with dichloromethane. The dichloromethane phases are concentrated in vacuo to give 0.35 g of 4-(pyrrolidin-1-ylmethyl)-1,3-oxazolidin-2-one a92 as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19]2[S:32][CH:31]=[CH:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:39][CH2:40][CH2:41][CH2:42]Br>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:42][CH2:41][CH2:40][Br:39])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19]2[S:32][CH:31]=[CH:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCCBr)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Temperature: 100 °C
Yield: 42 %

Procedure:
To a solution of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-hydroxy-indole-1-carboxylic acid tert-butyl ester (195 mg, 0.43 mmol, Example 5D) in 1,3-dibromopropane (2 mL) is added cesium carbonate (350 mg, 1.08 mmol). The resulting suspension is heated at 100° C. for 30 minutes. It is then filtered and concentrated. The residue is chromatographed through silica gel (ethyl acetate-n-heptane, 05:95 to 20:80 as eluant) to provide 103 mg (42%) of 5-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester as a yellow glass. LC/MS: RT=4.38 minutes, 576.11 m/e.
Reaction SMILES: [CH:1]([O:4][P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[OH:6])([CH3:3])[CH3:2].[Na].[C:12](#[N:15])[CH:13]=[CH2:14]>>[C:12]([CH2:13][CH2:14][P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:6])[O:4][CH:1]([CH3:3])[CH3:2])#[N:15]
Reactant: CC(C)OP(O)C(C)(C)C
Reactant: C=CC#N
Agent: [Na]
Product: CC(C)OP(=O)(CCC#N)C(C)(C)C

Procedure:
To 15.7 g of t-butylphosphonous acid-isopropylester in 6.3 ml of acrylonitrile are added 21 ml of sodium isopropylate (0.25 molar). After the exothermic reaction (the temperature rises to 100°) the suspension is filtered, the filtrate evaporated and the residue distilled to yield isopropyl 2-cyanoethyl(t-butyl)phosphinate as an oil, b.p. 121°/8 Pa, nD20 =1.4480.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:19]>C(O)C>[NH2:19][C:11]1[CH2:12][CH:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH2:8][C:9](=[O:14])[CH:10]=1
Reactant: [NH4+]
Reactant: Cc1ccc(C2CC(=O)CC(=O)C2)s1
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1ccc(C2CC(=O)C=C(N)C2)s1
Yield: 81.4 %

Procedure:
A mixture of 5-(5-methyl-2-thienyl)cyclohexane-1,3-dione (4.16 g) and ammonium acetate (4.6 g) in ethanol (50 ml) was refluxed for 15 hours, and the reaction solution was concentrated under reduced pressure. To the residue was added water (60 ml), and the resulting crystals were filtered. The crystals were washed with water and toluene, and dried to give 1-amino-5-(5-methyl-2-thienyl)cyclohexen-3-one (3.37 g) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH3:11])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:19]1[CH2:22][CH2:21][CH2:20]1>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH3:11])=[C:6]([O:8][CH:19]2[CH2:22][CH2:21][CH2:20]2)[CH:7]=1
Reactant: CCOc1ccc(Br)cc1O
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1ccc(Br)cc1OC1CCC1
Temperature: 65 °C
Yield: 97.3 %

Procedure:
The intermediate 5-bromo-2-ethoxy-phenol (15 g, 73.9 mmol) was dissolved in DMF (100 mL) then treated with anhydrous K2CO3 (20.4 g, 148 mmol) followed by the addition of bromocyclobutane (19.1 g, 128 mmol). The reaction was heated at 65° C. for 12 h, then cooled to room temperature, diluted with diethyl ether, and the solution washed with a 1 N aqeuous NaOH solution followed by water. The organic layer was then dried over MgSO4, filtered, and concentrated to afford titled compound as an oil (19.5 g, 90%). 1H NMR (CDCl3) 6.98 (dd, J=8.4, 2.1, 1H), 6.83 (d, J=2.4, 1H), 6.73 (d, J=8.7, 1H), 4.65-4.57 (m, 1H), 4.05 (q, J=7.1, 2H), 2.50-2.42 (m, 2H), 2.30-2.18 (m, 2H), 1.90-1.81 (m, 1H), 1.73-1.63 (m, 1H), 1.44 (t, J=7.1, 3H). 13C NMR 148.2, 147.8, 123.4 (CH), 117.0 (CH), 114.7 (CH), 112.7, 72.5 (CH), 64.8 (CH2), 30.6 (CH2), 14.7 (CH3), 13.1 (CH2). LC/MS (Method B) 4.18 min, [M+1]+ 271/273.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:14])[O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([NH2:15])[N:5]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:3]=1.[H-].[Na+].I[CH2:36][CH3:37]>>[NH2:1][C:2]1[C:7]([N:8]([CH2:36][CH3:37])[C:9](=[O:14])[O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([NH2:15])[N:5]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:3]=1
Reactant: CC(C)OC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Product: CCN(C(=O)OC(C)C)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N

Procedure:
Prepared in analogy to Example 6 with 60 mg (0.14 mmol) of isopropyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate from Example 3, 4.95 mg (0.21 mmol) of sodium hydride and 21.4 mg (0.17 mmol) of iodoethane. To complete the reaction, the same amount of sodium hydride and iodoethane are added once again. The residue is purified by preparative RP-HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C(N1CCOCC1)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(CCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Reactant: NCC(=O)O
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCC(=O)NCC(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 7.1 %

Procedure:
To a solution of p-nitrophenyl 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionate (187 mg, 0.5 mmol) and glycine (37 mg, 0.5 mmol) in N,N-dimethylformamide (5 ml) was added N-ethylmorpholine (128 μ1, 1.0 mmol). The mixture was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was chromatographed on a Sephadex, LH20 column (1.5×90 cm, eluent: ethanol). The eluate was evaporated and the residue was crystallized from ethyl ether to give 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinone-6-yl)propionyl-glycine (11 mg), melting at 128°-130° C. Rf=0.34 (Chloroform-methanol-acetic acid (18:2:1), silica gel plate) (briefly Rf1), Rf=0.52 (Ethyl acetate-pyridine-acetic acid-water (60:20:6:10, v/v, silica gel plate) (briefly Rf2).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22]([OH:24])=O)[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:4]=1[CH3:36])#[N:2].C[N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22]([NH2:38])=[O:24])[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)[C:4]=1[CH3:36])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(N)=O)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 94.4 %

Procedure:
The reaction was carried out under argon. 2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (90 mg, 174 μmol; Example 21) was initially charged in DMF (3 ml), HATU (330 mg, 868 μmol, 5 eq.) was added at 0° C. and the mixture was stirred for 20 min. Ammonium chloride (18.1 mg, 340 μmol, 5 eq.) and N,N-diisopropylethylamine (224 mg, 1736 μmol, 10 eq.) were then added, and the mixture was stirred at RT until complete conversion had been achieved (after a number of hours; HPLC control). The reaction mixture was then concentrated under reduced pressure, and the crude product was purified by preparative HPLC (Column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (85 mg, 94% of theory).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:16]([OH:18])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.Cl.[NH2:20][C@@H:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22]([NH2:24])=[O:23]>>[C:22]([C@@H:21]([NH:20][C:16]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])[N:8]=1)=[O:18])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:23])[NH2:24]
Reactant: NC(=O)[C@@H](N)c1ccccc1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)F)n1
Agent: Cl
Product: NC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCC(F)(F)F)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 280c, using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 301a) and (S)-2-amino-2-phenyl-acetamide hydrochloride (CAN 60079-51-8) as starting materials, MS (EI): m/e=394.1 [M+H]+.