Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[Cl:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](=[O:15])[CH2:8][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: Cc1cc(Cl)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1cc(Cl)ccn1)c1ccc(Cl)cc1

Procedure:
To a solution of 4-chloro-2-methylpyridine (23.07 g, 181 mmol) and methyl 4-chlorobenzoate (30.8 g, 181 mmol) in dry THF (500 mL) at 0° C. was added 1 M LiHMDS in THF (63.5 g, 380 mmol) slowly via a dropping funnel. When complete, the reaction was quenched with NaHCO3 solution, concentrated under reduced pressure, and extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].C(C1C=CC=C(C(C)C)C=1[N+]1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C=1)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cccc(C(C)C)c1-n1cc[n+](-c2c(C(C)C)cccc2C(C)C)c1
Product: Cc1cccc(C#CC=C2CCN(c3ccc(C#N)nc3)CC2)n1
Temperature: 110 °C
Yield: 10.3 %

Procedure:
A mixture of the compound of Example 3 (0.102 g, 0.48 mmol), 5-bromo-2-cyanopyridine (0.073 g, 0.40 mmol), cesium carbonate (0.658 g, 2 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (8.8 mg, 0.05 mmol), palladium(II)acetate (0.0046 mg, 0.05 mmol), in anhydrous and degassed THF (3 mL) was heated in a microwave oven at 110° C. for 15 min in a sealed vessel. The reaction mixture was cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether 1:1) affording the title product (0.013 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[NH2:32][CH:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:34]1>>[CH2:38]([N:35]1[CH2:36][CH2:37][CH:33]([NH:32][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:30])[F:29])[C:9]=4[CH:17]=3)[CH:19]=2)[CH2:34]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NC1CCN(Cc2ccccc2)C1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3-amino-1-benzylpyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z=604.99 (M+H+); retention time=0.63 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([NH:18]C(=O)OCC3C=CC=CC=3)=[CH:8][C:9]=1[NH:10]2.Br>CCOCC>[BrH:1].[NH2:18][C:7]1[CH:8]=[C:9]2[C:4]([C:3]3[C:2]([Br:1])=[CH:14][CH:13]=[C:12]([C:15]([NH2:16])=[O:17])[C:11]=3[NH:10]2)=[CH:5][CH:6]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(NC(=O)OCc3ccccc3)ccc12
Agent: Br
Solvent: CCOCC
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(N)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of benzyl 5-bromo-8-carbamoyl-9H-carbazol-2-ylcarbamate (Example 50-3, 2.18 g, 4.97 mmol) in hydrogen bromide (30-35% in acetic acid, 11.9 mL, 59.7 mmol) was stirred at rt for 30 min. The mixture was diluted with ether (100 mL) and the precipitate was collected by filtration, washed with ether and dried to provide 7-amino-4-bromo-9H-carbazole-1-carboxamide, hydrobromide salt, as a light yellow solid (2.20 g). 1H NMR (400 MHz, DMSO-d6) δ 12.02 (1 H, s), 8.69 (1 H, d, J=8.5 Hz), 8.28 (1 H, br. s.), 7.91 (1 H, d, J=8.0 Hz), 7.84 (1 H, d, J=1.8 Hz), 7.65 (1H, br. s.), 7.51 (1 H, d, J=8.3 Hz), 7.25 (1 H, dd, J=8.4, 1.9 Hz). Mass spectrum m/z 304, 306 (M+H)+. The salt was partitioned between EtOAc and NaHCO3 (aq). Residual solid was collected by filtration, washed with EtOAc and water and dried. The organic phase of the filtrate was separated, washed with brine, and dried and concentrated. The solid residue was combined with the filtered solid, dissolved in acetone, filtered to remove undissolved solid, and the filtrate was concentrated to provide 7-amino-4-bromo-9H-carbazole-1-carboxamide, hydrobromide salt, as a light yellow solid (1.62 g, 96%).
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[CH3:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[CH3:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(OCC(=O)O)c2F)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[5-(3-fluorophenyl)-2,3-dimethyl-phenyl]methylamino]phenoxy]acetate (120 mg, 0.27 mmol, 1.0 eq.) in a mixture of THF (5 mL) and MeOH (5 mL) at room temperature was added NaOH (2M aqueous solution, 5 mL, 10 mmol). The reaction was stirred at room temperature for 3 h. The reaction was then diluted with EtOAc and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) filtered and evaporated in vacuo to give the title compound as a gummy solid (112 mg, 94%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:19]>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[C:3]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:19]
Reactant: O=C(Nc1ccccn1)C1=C(O)c2ccccc2N(c2ccccc2)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: O=C(Nc1ccccn1)c1cn(-c2ccccc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
A solution of 2.4 g of 1,2-dihydro-4-hydroxy-1-phenyl-N-(2-pyridyl)-3-quinolinecarboxamide in 150 ml of benzene was treated with 8.4 g of activated manganese dioxide. The slurry was stirred at room temperature for 30 minutes, filtered, and evaporated. Recrystallization of the residue from dichloromethane-diethyl ether afforded 2.19 g (92%) of 1,4-dihydro-4-oxo-1-phenyl-N-(2-pyridyl)-3-quinolinecarboxamide, m.p. 238°-240° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[C:17]1([C:14]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:16][CH2:15]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)NCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 48 h
Yield: 78.2 %

Procedure:
Diketene (0.44 mL, 5.68 mmol, 1.3 equiv, Aldrich) was added at room temperature to a stirred solution of 1-(3-aminopropyl)-4-,4-diphenylpiperidine (1.288 g, 4.37 mmol, 1.0 equiv) in anhydrous toluene (15 mL) under argon, and stirring was continued for 48 hours. The mixture was concentrated to give 1.294 g (78%) of white solid, which was used for the next reaction without purification: 1H NMR (300 MHz, CDCl3) δ 1.70 (tt, J=6.4, 6.4 Hz, 2H), 2.23 (s, 3H), 2.44 (br t, J=6.5 Hz), 2.49-2.67 (m, 8H), 3.32 (br t, J=5.8 Hz), 3.36 (s, 2H), 7.16 (m, 2H), 7.27 (m, 8H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][C:8]([C:18]1[CH:17]=[CH:16][C:15]2[O:11][CH2:12][CH2:13][C:14]=2[CH:19]=1)=[O:9]
Reactant: c1ccc2c(c1)CCO2
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCCl)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.8 %

Procedure:
To a solution of AlCl3 (2.22 g, 1.0 eq) in 50 mL CH2Cl2 was added 3-chloropropanoyl chloride (2.54 g, 1.2 eq) dropwise. The mixture was stirred at rt for 10 min, then 2,3-dihydrobenzofuran (2.0 g, 1.0 eq) was added. After stirring at rt overnight, the mixture was quenched with cold water and then extracted with CH2Cl2. The extract was dried over Na2SO4, filtered, the filtrate was concentrated and purified by column chromatography on silica gel to give the desired product (1.5 g, 62%). 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.68 (t, J=8.8 Hz, 2H), 3.92 (t, J=6.8 Hz, 2H), 3.40 (t, J=8.8 Hz, 2H), 3.26 (t, J=6.8 Hz, 2H).
Reaction SMILES: [CH3:1][CH2:2][NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH3:18])=[O:17])=[CH:11][CH:10]=1)=[O:8].[CH:19]1C=CC2N(O)N=NC=2[CH:24]=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][CH2:2][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([CH3:18])=[O:17])=[CH:13][CH:14]=1)=[O:8])[CH2:19][CH3:24]
Reactant: CCNCCNC(=O)c1ccc(NC(C)=O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1ccc(NC(C)=O)cc1
Reaction time: 8 h

Procedure:
The N-Acetylprocainamide probe was prepared as follows: 1.0 mg desethyl-N-Acetylprocainamide was placed in a 3.0 ml reaction vial and dissolved with 100 μl DMF. In a separate vial, caged dicarboxy silicon phthalocyanine (1.0 mg) was dissolved in 400 μl DMF and then transferred to the reaction vial along with 200 μl of wash DMF for a total of 600 μl. To the reaction vial was added 4.2 mg HOBT, dissolved and mixed well. To make the final reaction mixture, 10.5 mg EDAC was added and mixed thoroughly. The reaction mixture was stirred overnight at about 4° to 8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].C1COCC1.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
An 18-mL vial was charged with methyl 2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetate (31 mg, 0.77 mmol, 1 eq.) and lithium hydroxide monohydrate (48 mg, 1.14 mmol, 1.48 eq.). To this was added THF (1 ml) and water (0.5 ml). The resulting mixture was stirred at room temperature overnight. Then 2N HCl aq. (0.6 ml) was added. The volatile materials were removed under reduced pressure to give a residue, which was purified by chromatography on silica gel using 2˜5% of MeOH in dichloromethane as eluent to give 2-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetic acid (26 mg, HCl salt, 81% yield). MW=378.85. 1H NMR (DMSO-D6, 360 MHz) δ 14.23 (brs, 1H), 12.39 (brs, 1H), 9.84 (brs, 1H), 7.91 (s, 1H), 7.70 (d, J=7.70 Hz, 1H), 7.63 (d, J=8.40, 1H), 7.57 (dd, J=7.70, 8.40 Hz, 1H), 7.36 (brs, 4H), 7.02 (s, 1H), 3.60 (s, 2H), 3.11 (t, J=7.90 Hz, 2H), 2.90 (t, J=7.40 Hz, 2H), 2.20 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1.Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1
Reactant: COC(=O)c1ccc(CN)cc1F
Reactant: O=S(=O)(Cl)CCCCl
Product: COC(=O)c1ccc(CN2CCCS2(=O)=O)cc1F

Procedure:
Using methyl 4-aminomethyl-2-fluorobenzoate (181 mg) described in Preparation Example 199 and 3-chloropropane-1-sulfonyl chloride (0.14 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (233 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:9].[Na+].[I-].O[CH2:13][CH:14]([CH2:16]O)O.[OH-].[Na+]>OS(O)(=O)=O>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]2[C:4]([CH:13]=[CH:14][CH:16]=[N:9]2)=[CH:5][CH:6]=1
Reactant: OCC(O)CO
Reactant: Nc1cccc(N)c1Cl
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Product: Nc1ccc2cccnc2c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.7 %

Procedure:
To a mixture of 2-chlorobenzene-1,3-diamine (24 mmol) (CAS 6400-14-2) and NaI (150 mg) in 80% H2SO4 (20 g) was added Glycerol (45 g). The mixture was stirred at 150° C. to 170° C. for 5 h. The mixture was cooled to room temperature. Aqueous 5N NaOH was used to adjust the pH to alkaline, which was then extracted with EtOAc washed with brine, dried over MgSO4 and concentrated under reduced vacuum. Flash column chromatography (EtOAc:Hexane) yielded 7-amino-8-chloroquinoline (800 mg), as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ: 8.69 (dd, J=4.4, 1.8 Hz, 1H), 8.13 (dd, J=7.9, 1.8 Hz, 1H), 7.61 (d, J=9.1 Hz, 1H), 7.14-7.29 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[O:17])[N:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)[C:12]2=[CH2:28])=[CH:7][CH:6]=1)=[O:4].[H][H]>CN(C)C=O.[Pd]>[CH3:27][O:26][C:24]([C:21]1[CH:22]=[CH:23][C:18]([N:13]2[C:14](=[O:17])[C:15](=[O:16])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH:12]2[CH3:28])=[CH:19][CH:20]=1)=[O:25]
Reactant: C=C1N(c2ccc(C(=O)OC)cc2)C(=O)C(=O)N1c1ccc(C(=O)OC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2C(=O)C(=O)N(c3ccc(C(=O)OC)cc3)C2C)cc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A solution of 40.8 g (0.1 mole) of 1,3-bis-(4'-methoxycarbonylphenyl)-2-methylene-imidazolidine-4,5-dione in 500 ml of dimethylformamide is hydrogenated in a laboratory hydrogenating apparatus, after addition of 2 g of a 5% palladium on charcoal catalyst, at room temperature and with vigorous stirring under slight hydrogen overpressure, until the uptake of hydrogen has ceased. The catalyst is filtered off and the solution is poured into 3 liters of ice water with vigorous stirring. The precipitated product is recrystallised from xylene, to yield 32 g of colourless crystals with a melting point of 250° C. The IR and NMR spectra confirm the presumed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][C@H:22]4[CH2:27][CH2:26][C@H:25]([C:28]([O:30]C)=[O:29])[CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][C@H:22]4[CH2:27][CH2:26][C@H:25]([C:28]([OH:30])=[O:29])[CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)[C@H]1CC[C@H](CNc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@H](CNc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1

Procedure:
Prepared from compound 244 of Example 1 by reaction with sodium hydroxide in a methanol/tetrahydrofuran mixture.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].[CH2:9]([N:11]([CH2:32][CH3:33])[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2C=C(C3C=CSC=3)[NH:24][N:23]=2)=[CH:17][CH:16]=1)[CH3:10]>C(Cl)Cl.CO>[CH2:32]([N:11]([CH2:9][CH3:10])[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[CH:2]=[C:1]([C:4]3[S:5][CH:6]=[CH:7][CH:8]=3)[NH:24][N:23]=2)=[CH:17][CH:16]=1)[CH3:33]
Reactant: CC(=O)c1cccs1
Reactant: CCN(CC)CCOc1ccc(Nc2cc(-c3ccsc3)[nH]n2)cc1
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(Nc2cc(-c3cccs3)[nH]n2)cc1

Procedure:
The title compound is prepared as described in Example 33 but using 2-acetylthiophene and diethyl-[2-(4-isothiocyanato-phenoxy)-ethyl]-amine (Example 37). Title compound: ES-MS: 357.1 [M+H]+; single peak at tR=2.98 min (System 2); Rf=0.11 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:13](C1CCC(=O)CC1)([CH3:16])([CH3:15])[CH3:14].N1CCOCC1>C1CCCCC1>[C:13]([CH:4]1[CH2:5][CH2:6][C:1]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:2][CH2:3]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: CC(C)(C)C1CCC(=O)CC1
Solvent: C1CCCCC1
Solvent: C1COCCN1
Product: CC(C)(C)C1CC=C(N2CCOCC2)CC1

Procedure:
Compound III′ (white solid) is obtained quantitatively according to Example 1, from 4-tert-butylcyclohexanone (77.12 g, 0.50 mol), morpholine (54.01 g, 0.62 mol) and cyclohexane (60 mL).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=O)[N:6]=1)([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:25]2[CH2:30][CH2:29][O:28][C:26]2=[O:27])C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=[C:25]2[CH2:30][CH2:29][O:28][C:26]2=[O:27])[N:6]=1)([CH3:1])[CH3:3]
Reactant: O=C1OCCC1=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(C=C2CCOC2=O)nc(C(C)(C)C)c1O
Yield: 62.6 %

Procedure:
A solution of 4,6-bis(1,1-dimethylethyl)-5-hydroxypyrimidine-2-carboxaldehyde (0.5 g, 2.1 mmol) and α-triphenylphosphoranylidene-γ-butyrolactone (Katsumi, et al. Chem. Pharm. Bull. [Japan] 1986, 34, 619) (0.95 g, 2.8 mmol) in 50 mL of toluene is warmed to 60° C. overnight. The toluene is evaporated and the residue purified by flash chromatography (silica, 20% EtOAc/hexane). Recrystallization from hexane gives 0.4 g (62%) of α-[[4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]methylene]-γ-butyrolactone, mp 158°-160° C.
Reaction SMILES: C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.Br[C:27]1[N:32]=[C:31]([NH:33][C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=2)[CH:30]=[C:29]([CH3:44])[CH:28]=1.[OH:45][C@:46]1([C:60]2[S:61][CH:62]=[CH:63][N:64]=2)[CH2:55][CH2:54][CH2:53][C:52]2[CH:51]=[C:50]([C:56]([O:58][CH3:59])=[O:57])[CH:49]=[CH:48][C:47]1=2.[F-].[Cs+].C(O)(=O)C(C)(C)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:45][C@:46]1([C:60]2[S:61][C:62]([C:27]3[CH:28]=[C:29]([CH3:44])[CH:30]=[C:31]([NH:33][C:34]4[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=4)[N:32]=3)=[CH:63][N:64]=2)[CH2:55][CH2:54][CH2:53][C:52]2[CH:51]=[C:50]([C:56]([O:58][CH3:59])=[O:57])[CH:49]=[CH:48][C:47]1=2
Reactant: COC(=O)c1ccc2c(c1)CCC[C@]2(O)c1nccs1
Reactant: Cc1cc(Br)nc(Nc2cc(C(F)(F)F)ccn2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)CCC[C@]2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.2 %

Procedure:
A suspension of butyl di-1-adamantylphosphine (5.95 g, 16.59 mmol) and Pd(OAc)2 (1.862 g, 8.29 mmol) in 1,4-dioxane (100 mL) was stirred under nitrogen for 10 minutes and a yellow slurry was formed. 6-Bromo-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (17.39 g, 52.4 mmol), (R)-methyl 5-hydroxy-5-(thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (enantiomer 2, 12 g, 41.5 mmol), cesium fluoride (18.90 g, 124 mmol), pivalic acid (7.22 mL, 62.2 mmol) and 1,4-dioxane (50 mL) were then added. The reaction mixture was vacuum purged with nitrogen 3 times and then heated to reflux under nitrogen for 20 hours. The reaction was cooled to rt and filtered through Celite®, washing through with EtOAc. The organic filtrate was washed sequentially with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 40% ethyl acetate in hexanes to afford the (R)-methyl 5-hydroxy-5-(5-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a pale yellow solid (18 g, 80% yield). MS ESI calcd for C27H23F3N4O3S [M+H]+ 541, found 541. 1H NMR (500 MHz, DMSO) δ 10.20 (s, 1H), 8.63 (s, 1H), 8.48 (d, J=5.0 Hz, 1H), 8.23 (s, 1H), 7.74 (s, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.36 (s, 1H), 7.23-7.17 (m, 2H), 7.09 (s, 1H), 6.63 (s, 1H), 3.82 (s, 3H), 2.92-2.85 (m, 2H), 2.33-2.30 (m, 4H), 2.15-2.09 (m, 1H), 2.02-1.88 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH2:25][O:26][C:27]([F:30])([F:29])[F:28])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:34])[F:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH2:25][O:26][C:27]([F:30])([F:29])[F:28])[C:17]([OH:19])=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CCOC(F)(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CCOC(F)(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
327 mg (0.62 mmol) of tert-butyl 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-(trifluoromethoxy)butanoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 290 mg (purity 93%, 92% of theory)
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3].N(/C(C)(C)C#N)=N\C(C)(C)C#N.C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:29][CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccccn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)/N=N/C(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(Br)c1ccccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 2-propylpyridine (2.5 g, 20.63 mmol, purchased from Sigma-Aldrich, St. Louis, Mo.) and (E)-2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (1.253 g, 7.63 mmol, purchased from Sigma-Aldrich) in CCl4 (60 mL) at rt was added n-bromosuccinimide (1.93 mL, 22.7 mmol, purchased from Sigma-Aldrich). The mixture was stirred under fluorescent light at rt for 12 hr. The precipitate was removed by filtration of the mixture through a pad of Celite® (J.T. Baker, Phillipsberg, N.J., diatomaceous earth), which was washed with CCl4 (10 mL). The filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 20% EtOAc/hexanes) provided the title compound as a yellow liquid. Mass Spectrum (ESI) m/z=199.9 and 201.9 (M+1).