Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:28]=[C:27](F)[CH:26]=[CH:25][C:22]=1[CH:23]=[O:24].O>CS(C)=O>[F:20][C:21]1[CH:28]=[C:27]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)c(F)c2)CC1
Reaction time: 8 h
Yield: 48.7 %

Procedure:
9.17 g (49.3 mmol) of tert-butyl piperazine-1-carboxylate and then 6.81 g (49.3 mmol) of potassium carbonate, respectively, are added to 7 g (49.3 mmol) of 2,4-difluorobenzaldehyde diluted in 60 ml of dimethylsulfoxide. The solution is carried at 60° C. for 8 hours and then water is added and the product is extracted several times with ethyl acetate. The organic phases are combined, dried on magnesium sulfate and concentrated. The residue obtained is purified by silica gel chromatography (eluent: 7:3 cyclohexane/ethyl acetate) to yield 7.4 g (48%) of tert-butyl 4-(3-fluoro-4-formylphenyl)piperazine-1-carboxylate in the form of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[CH:16][N:15]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14]=2[CH:31]=1)=[O:8])([O-])=O.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[CH:16][N:15]([CH:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14]=2[CH:31]=1)=[O:8]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3cccc([N+](=O)[O-])c3)cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3cccc(N)c3)cc21
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-{6-[(3-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (231 mg, 504 μmol) in a mixture of ethanol and water (4:1, 10 mL), was added palladium on carbon (46 mg, 10% w/w Pd) and ammonium formate (191 mg, 3.03 mmol). The suspension was heated to reflux for 3 hours, and was then cooled to room temperature, and filtered through a pad of Celite®. The filtrate was evaporated in vacuo to afford the title compound, 1H NMR: (CD3OD), 8.43 (s, 1H), 8.14 (d, J=1.46, 1H), 7.65 (d, J=8.79, 1H), 7.47 (dd, J=8.79, 1.83, 1H), 7.30 (br, 8H), 6.92-6.90 (m, 1H), 6.11 (dd, J=9.52, 6.22, 1H), 4.04 (q, J=7.32, 2H), 3.62 (dd, J=16.11, 9.52, 1H), 3.46 (dd, J=16.11, 6.22, 1H), 1.08 (t, J=7.32, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](F)[C:3]=1[C:13]([CH3:15])=[CH2:14].[CH3:16][S-:17].[Na+].CCOCC>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:17][CH3:16])[C:3]=1[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)c1c(Cl)ccc(C(=O)OC)c1F
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(C)c1c(Cl)ccc(C(=O)OC)c1SC
Temperature: 50 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
A mixture of methyl 4-chloro-2-fluoro-3-isopropenylbenzoate (8.6 g) and sodium thiomethoxide (3.15 g) in dimethyl formamide was heated at 50° C. for 3 hours and stirred at room temperature overnight. Ether was added and the mixture was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography eluted with a mixture of ethyl acetate and hexane to give methyl 4-chloro-3-isopropenyl-2-(methylsulphenyl)benzoate (5.95 g) as a clear oil NMR (CDCl3) 2.1(s,3H), 2.35(s,3H), 3.95(s,3H), 4.9(s,1H), 5.4(s,1H), 7.45(s,2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]([C:10](=[O:30])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[C:19](=O)[NH:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]([C:10]1[O:30][CH:19]([NH:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[C:13]2[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cccc(Cl)c1C(=O)Nc1cc(F)cc(F)c1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)OC(C)(C)C)C1=Nc2cccc(Cl)c2C(Nc2cc(F)cc(F)c2)O1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A 100-mL, three-neck, round bottomed flask equipped with a magnetic stirrer and thermometer was purged with nitrogen and charged with compound 168 (3.30 mmol), anhydrous methylene chloride (25 mL), N,N-diisopropylethylamine (4.60 g, 35.7 mmol) and triphenylphosphine (3.98 g, 15.2 mmol). The reaction mixture was then cooled to 0-5° C. in an ice/water bath. Iodine (3.61 g, 14.2 mmol) was then added portion-wise to the reaction mixture over 1 h. Once the addition was complete, the cooling bath was removed, and the mixture was stirred at room temperature for an additional 30 min. The reaction was then quenched with 10% aqueous potassium carbonate (25 mL), the organic layer separated, dried over sodium sulfate, filtered concentrated under reduced pressure. Column chromatography of the resulting-solid (silica gel, EtOAc/hexanes) gave a 52% yield of compound 169 as a white solid. m.p. 117-118° C.; 1H NMR (DMSO-d6) δ (ppm) 7.72-7.60 (m, 2H), 7.42 (dd, 1H, J=7.6 Hz, 1.3 Hz), 7.31 (d, 1H, J=7.0 Hz), 6.95 (t, 1H, J=9.3 Hz), 6.82 (m, 2H), 4.27 (m, 1H), 1.33 (s, 9H), 1.28 (d, 3H, J=7.2 Hz); m/z=436 (M+H). The reaction described above and compound 169 are shown below.
Reaction SMILES: Br[CH:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[O:4][CH2:3]1.[CH2:15]([NH:18][CH2:19][C:20](=[O:22])[CH3:21])[CH2:16][CH3:17]>C1(C)C=CC=CC=1.[N+](C)([O-])=O>[CH3:14][O:13][C:8]1[CH:7]=[CH:6][C:5]2[O:4][CH2:3][CH:2]3[N:18]([CH2:15][CH2:16][CH3:17])[CH2:19][C:20](=[O:22])[CH:21]=[C:11]3[C:10]=2[CH:9]=1
Reactant: CCCNCC(C)=O
Reactant: COc1ccc2c(c1)C(=O)C(Br)CO2
Solvent: Cc1ccccc1
Solvent: C[N+](=O)[O-]
Product: CCCN1CC(=O)C=C2c3cc(OC)ccc3OCC21

Procedure:
A mixture of 3-bromo-6-methoxy-4-chromanone (2.57 g) and 3.3 g of the ethylene ketal of 1-(propylamino)-2-propanone in 500 ml of toluene if refluxed for 17 hours. The resulting product is dissolved in 20 ml of nitromethane and added to 50 ml of 85% polyphosphoric acid. After 48 hours at room temperature the reaction is poured onto ice to afford 2,3,4a,5-tetrahydro-9-methoxy-4-propyl-4H-[1]-benzopyrano[3,4-b]pyridin-2-one.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:18])[C:4]1[S:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:8]=1>CCO.[Fe]>[CH3:2][N:3]([CH3:18])[C:4]1[S:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[N:8]=1
Reactant: CN(C)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CN(C)c1nc(-c2ccc(N)cc2)cs1
Yield: 87 %

Procedure:
Iron powder (6.51 g, 116.7 mmol) and 1N aqueous HCl (2.3 mL) were added to a solution of N,N-dimethyl-4-(4-nitrophenyl)-2-thiazolamine of section a) (2.91 g, 11.7 mmol) in EtOH (39 mL) at room temperature. The mixture was stirred and heated at reflux for 3 h. The hot reaction mixture was filtered through diatomaceous earth. The solid on the filter was washed with hot EtOH (200 mL). The filtrate was diluted with EtOAc and Et2O (1:1, 100 mL) and then concentrated to about 25% of its original volume. This solution was diluted with EtOAc (150 mL). The mixture was washed successively with saturated aqueous NaHCO3, H2O and brine, then dried (MgSO4) and concentrated under reduced pressure to give N,N-dimethyl-4-(4-aminophenyl)-2-thiazolamine (2.24 g, 87% yield) as a light brown oil: 1H NMR (400 MHz, DMSO-d6) δ7.53 (d, J=8.4 Hz, 2H), 6.74 (s, 1H), 6.56 (d, J=8.4 Hz, 2H), 5.16 (s, 2H), 3.05 (s, 6H); MS (FAB) m/z 220 (MH)+. This product was used without further purification in the next section.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C1(C)C=CC=CC=1>[N:1]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: COC1CCC(OC)O1
Reactant: N#Cc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-n2cccc2)cc1
Yield: 60.2 %

Procedure:
A mixture of 4-aminobenzonitrile (50 g., 0.42 mole), 2,5-dimethoxytetrahydrofuran (56 g., 0.42 mole) and 4A molecular sieves (184 g) in toluene (560 ml) was heated under reflux for 24 hrs. The residue from evaporation was washed with pet. ether and then recrystallized from diisopropyl ether to yield 42.5 g (60%) of 4-(1-pyrrolyl)benzonitrile, m.p. 104°-106° C.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.[Na+].[I-]>CN(C)C=O>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:12]([C:10]2[S:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:26][CH:25]=1
Reactant: O=C(Nc1ccc(-c2ccccc2)s1)c1ccccc1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N(Cc1ccc(Cl)cc1)c1ccc(-c2ccccc2)s1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
The amide of Example 53 (2.8 g, 0.01 mole) in dimethylformamide (25 ml.) was added to sodium hydride (0.0105 mole) (from 40-50% NaH in oil, 0.74 g) which was stirred in dimethylformamide (25 ml.) and cooled in ice. The mixture was stirred for 0.5 hr. and treated with a solution of p-chlorobenzyl chloride (3.22 g, 0.02 mole) in DMF (15 ml.) and a trace of NaI. The mixture was stirred, initially at ice-bath temperature and them at room temperature overnight and then refluxed for 3 hours to complete the reaction. The DMF was evaporated off, water was added, the product extracted with chloroform, which was dried (Na2SO4), filtered and evaporated to give the N-p-chlorobenzyl-benzamide (2.07 g.) as a viscous oil, b.p. 240°-245° C./0.35 mm.Hg.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]#[N:19])[CH:12]=2.[CH3:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[C@@H:31]1[CH2:33][O:32]1>CCO>[OH:32][C@H:31]([C:22]1[CH:23]=[CH:24][C:25]2[C:26](=[O:30])[O:27][CH2:28][C:29]=2[C:21]=1[CH3:20])[CH2:33][N:6]1[CH2:5][CH2:4][N:3]([C:8]2[N:9]=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([C:18]#[N:19])[CH:12]=3)[C:2](=[O:1])[CH2:7]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: N#Cc1ccc2cc(N3CCNCC3=O)ncc2c1
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(c3cc4ccc(C#N)cc4cn3)C(=O)C2)ccc2c1COC2=O
Temperature: 145 °C

Procedure:
A mixture of 3-(2-oxopiperazin-1-yl)isoquinoline-7-carbonitrile [I-6] (20 mg, 0.079 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (30 mg, 0.16 mmol) in EtOH (1 mL) in a 5 mL microwave tube was heated to 145° C. for 1.5 hours. LC showed formation of title product, which was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 443 [M+1]+.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:32])[CH:15]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=2)[CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=1.[H][H]>CC(O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]([OH:32])[C@@H:15]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:30][CH:31]=2)[CH2:16][CH2:17][CH3:18])=[CH:12][CH:13]=1
Reactant: CCCC(C(=O)c1ccc(Cl)cc1)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: [H][H]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCC[C@H](c1ccc(C(=O)OC(C)(C)C)cc1)[C@@H](O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To degassed 2-propanol (5.0 mL) was added RuCl2-[(8)-xyl-SEGPHOS][(S)-DAIPEN] (16.2 mg, 0.0134 mmol) and potassium t-butoxide (300 mg, 2.67 mmol). After this mixture was stirred at room temperature for 2 hours, the material obtained in Step A was added in 2-propanol (25 mL). This mixture was then treated with hydrogen (100 psi) at room temperature for 18 hours. The mixture was concentrated, then the residue was recrystallized from IPA/water to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.96 (m, 2H), 7.32 (m, 2H), 7.26 (m, 2H), 7.22 (m, 2H), 4.76 (dd, J=7.7, 2.9 Hz, 1H), 2.89 (ddd, J=11.5, 7.7, 4.2 Hz, 1H), 1.84 (d, J=2.9 Hz, 1H), 1.62 (s, 9H), 1.61 (m, 1H), 1.41 (m, 1H), 1.05 (m, 2H), 0.76 (t, J=7.3 Hz, 3H); LC2: 2.38 min. (M−H2O-tBu+H)+ 301; Chiral SFC Method: Chiralpak AD-H (250×4.6 mm), isocratic 15% MeOH/CO2, 1.5 mL/min, 200 bar, 35° C., 215 nm, 15 minutes: desired alcohol retention time=9.8 min; enantiomeric alcohol, retention time=10.6 min; diastereomeric alcohols retention times=5.2 and 6.3 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:31]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[O:32])[CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Reactant: CN1CCN(C(=O)Cl)CC1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)N3CCN(C)CC3)C2)cc1

Procedure:
250 mg (0.74 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 156 mg (0.96 mmol, 1.3 eq.) of 4-methylpiperazine-1-carbonyl chloride were reacted according to General Method 3. Yield: 213 mg (66% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Solvent: c1ccncc1
Product: CS(=O)(=O)NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of EXAMPLE 11A (100 mg, 0.3 mmol) in pyridine (5 mL) was added methanesulfonyl chloride (50 mg, 0.4 mmol). The mixture was stirred at ambient temperature for 5 h and partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to provide the title compound. Yield: 100 mg (82%). MS (DCI/NH3) m/z 430 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:23]=2)=[N:10]1.Cl.[NH:34]1[CH2:39][CH2:38][O:37][CH:36]([CH2:40][C:41]([OH:43])=[O:42])[CH2:35]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[N:26]=[CH:25][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:23]=2)[NH:12][C:13]([CH2:20][N:34]2[CH2:39][CH2:38][O:37][CH:36]([CH2:40][C:41]([OH:43])=[O:42])[CH2:35]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)Cn1cnc(C2=NC(c3ccc(F)cc3Br)C(C(=O)OCC)=C(CBr)N2)n1
Reactant: O=C(O)CC1CNCCO1
Agent: Cl
Product: CCOC(=O)Cn1cnc(C2=NC(c3ccc(F)cc3Br)C(C(=O)OCC)=C(CN3CCOC(CC(=O)O)C3)N2)n1
Yield: 53.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.57 g, 1 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.3 g, 1.65 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.34 g, 53%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[C:13]([C:29]([F:32])([F:31])[F:30])=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[N:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[OH-].[Li+].O>>[NH2:23][C@@:22]([C:17]1[N:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[C:13]=2[C:29]([F:32])([F:30])[F:31])[N:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)C1CCC(Oc2ccc3nc([C@]4(C)COC(=O)N4)ncc3c2C(F)(F)F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc([C@@](C)(N)CO)ncc3c2C(F)(F)F)CC1
Temperature: 80 °C

Procedure:
(R)-4-[6-(4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-quinazolin-2-yl]-4-methyl-oxazolidin-2-one (180.0 mg, 0.0003987 mol) was dissolved in ethanol (7 mL, 0.1 mol), followed by 4 M lithium hydroxide in water (3 mL, 0.01 mol). The reaction mixture was then heated at 80° C. for 2 hours. All solvent was removed. The solid was extracted with DCM, and organic layers were dried over Na2SO4. Removal of solvent gave a pure product (152 mg, 90%). 1H NMR (MeOD) δ: 9.73 (s, 1H), 8.24 (d, J=9.3 Hz, 1H), 8.05 (d, J=9.5 Hz, 1H), 4.50-4.68 (m, 1H), 4.11 (d, J=11.0 Hz, 1H), 3.84 (d, J=11.0 Hz, 1H), 2.22 (d, J=10.8 Hz, 2H), 1.92 (d, J=13.1 Hz, 2H), 1.61 (s, 3H), 1.43-1.58 (m, 2H), 1.18-1.35 (m, 2H), 1.04-1.18 (m, 1H), 0.91 (s, 9H). MS (M+1): 426.30.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:17]=[CH:18][C:19]3[N:24]([CH3:25])[CH2:23][CH2:22][O:21][C:20]=3[CH:26]=2)[N:5]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[CH:18][C:19]3[N:24]([CH3:25])[CH2:23][CH2:22][O:21][C:20]=3[CH:26]=2)[N:5]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)OCCN2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)OCCN2C
Yield: 81.2 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-phenylpyrimidin-5-yl)pentanoate (0.075 g; 0.174 mmol), sodium hydroxide 10N (0.174 mL; 1.74 mmol) in methanol (1.7 mL) to afford 0.059 g (80%) of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17].Cl>CN(C=O)C>[C:3]1([S:9][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Sc1ccccc1
Reactant: CC(=O)OCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCSc1ccccc1
Temperature: 0 °C
Reaction time: 0.21 h

Procedure:
To a suspension of NaH (60%, 0.91 g, 23 mmol) in anhydrous DMF (20 mL) at RT is added dropwise benzenethiol (2.5 g, 22.7 mmol) in DMF (5 mL). The mixture is stirred for 10-15 min, at which time it becomes clear and yellow. The mixture is cooled to 0° C. in an ice bath then 4-bromobutylacetate (4.5 g, 22.8 mmol) in DMF (5 mL) is added dropwise and the mixture is stirred at RT for 1 h. The mixture is poured into 1N HCl (50 mL) and extracted with MTBE (2×). The combined organic extracts are washed with brine (2×) and dried over MgSO4. The solvent is removed under reduced pressure to afford the title compound as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncccc2C2=CCOCC2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncccc2C2CCOCC2)CC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
A mixture of tert-butyl 4-((3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)oxy)piperidine-1-carboxylate (see PREPARATION P28.1; 3.5 g, 9.6 mmol) and wet Pd—C (50%, 1.0 g) in MeOH (100 mL) was stirred under H2 (40 psi) at 30° C. overnight then the reaction mixture was filtered through CELITE® and washed with MeOH. The filtrate was concentrated to give of the desired compound (3.2 g, 8.1 mmol, yield 91%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH3:10].Br[CH2:23][CH:24]([CH3:26])[CH3:25]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:21])[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:10]
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Reactant: CC(C)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(CC(C)C)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 87.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (21.2 mL of a 0.31 M stock solution, 6.14 mmol) cooled to −78° C. was treated with (4-chloro-phenyl)-acetic acid ethyl ester (1.11 g, 5.58 mmol) in tetrahydrofuran/hexamethylphosphoramide (13.9 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of 1-bromo-2-methyl-propane (1.81 mL, 16.7 mmol) in hexamethylphosphoramide (1 mL). The mixture was stirred at −78° C. for 3 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The organics layers dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-4-methyl-pentanoic acid ethyl ester (1.24 g, 87.1%) as a white solid: mp 34-35° C.; EI-HRMS m/e calcd for C14H19ClO2 (M+) 254.1074, found 254.1069.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[C:28]([C:30]1[CH:31]=[C:32]([CH:40]([CH2:44][CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[C:41]([OH:43])=O)[CH:33]=[CH:34][C:35]=1[S:36]([CH3:39])(=[O:38])=[O:37])#[N:29].[NH2:50][C:51]1[S:52][CH:53]=[CH:54][N:55]=1>C(Cl)Cl>[C:28]([C:30]1[CH:31]=[C:32]([CH:40]([CH2:44][CH:45]2[CH2:46][CH2:47][CH2:48][CH2:49]2)[C:41]([NH:50][C:51]2[S:52][CH:53]=[CH:54][N:55]=2)=[O:43])[CH:33]=[CH:34][C:35]=1[S:36]([CH3:39])(=[O:38])=[O:37])#[N:29]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
A solution of triphenylphosphine (98 mg, 0.37 mmol) in methylene chloride (1 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (67 mg, 0.37 mmol). The reaction mixture was stirred at 0° C. for 15 min and then treated with 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.31 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (68 mg, 0.68 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (117 mg, 93%) as a white solid: mp 145-148° C.; EI-HRMS m/e calcd for C19H21N3O3S2 (M+) 403.1024, found 403.1023.