Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=[CH:35][C:32]=1[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][C:37]([O:41][CH3:42])=[C:38]([O:39][CH3:40])[C:31]=3[O:30][CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccc(C=O)c(OC)c1OC
Product: COc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(OC)c1OC

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,3,4-trimethoxybenzaldehyde to the procedure of step 1, Example 66. MS (ESI) m/z 559.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.Cl[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([C:25]4[CH:30]=[C:29]([C:31]5[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=5)[CH:28]=[CH:27][N:26]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccnc(Cl)c2)cc1
Reactant: Cc1ccc2c(n1)oc1c(B3OC(C)(C)C(C)(C)O3)cccc12
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccnc(-c3cccc4c3oc3nc(C)ccc34)c2)cc1
Yield: 71.1 %

Procedure:
A mixture of 2-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuro[2,3-b]pyridine (2.5 g, 8.03 mmol), 2-chloro-4-(p-tolyl)pyridine (1.80 g, 8.83 mmol), Pd2(dba)3 (0.147 g 0.161 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.264 g, 0.642 mmol), potassium phosphate (5.96 g, 28.1 mmol), toluene (100 mL) and water (10 mL) was degassed with nitrogen and then refluxed overnight. The reaction mixture was concentrated and extracted with ethyl acetate. The ethyl acetate layer was dried on Na2SO4 and then further purified by column chromatography using ethyl acetate in hexanes to give 2-methyl-8-(4-(p-tolyl)pyridin-2-yl)benzofuro[2,3-b]pyridine (2.0 g, 5.71 mmol, 71% yield).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:13][C:12]([CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C@H:10]1[C:20]([OH:22])=[O:21])=[O:8])(=O)C.N>>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:13][C:12]([CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C@H:10]1[C:20]([OH:22])=[O:21])=[O:8]
Reactant: CC(=O)SCCC(=O)N1CC(Cc2cccs2)=C[C@H]1C(=O)O
Agent: N
Product: O=C(O)[C@@H]1C=C(Cc2cccs2)CN1C(=O)CCS

Procedure:
The product from part (b) is treated with concentrated ammonia according to the procedure of Example 4 to yield (2S)-2,5-dihydro-1-(3-mercapto-1-oxopropyl)-4-[(2-thienyl)methyl]-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:14](\[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10](/[C:13](/[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:14](\[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)/[C:15]([F:16])([F:17])[F:18])=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=NCCOc1ccc(/C(=C(\c2ccccc2)C(F)(F)F)c2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: NCCOc1ccc(/C(=C(\c2ccccc2)C(F)(F)F)c2ccccc2)cc1
Reaction time: 1 h
Yield: 52.6 %

Procedure:
7.40 g (18 mmoles) of (E)-1-[4-(2-azidoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene, prepared as described in Example 7, are dissolved in 100 ml of methanol, 0.70 g of a 5% palladium-on-carbon catalyst are added, and the mixture is hydrogenated for about one hour. The catalyst is filtered off, the solution is evaporated, and the residue is crystallized from hexane. 3.63 g (52.3%) of the aimed compound are obtained; m.p.: 71°-76° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1.O>[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CO)cn1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(CCl)cn1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
To a solution of (6-methyl-3-pyridyl)-methanol (50 g, 0.506 mol) in toluene (500 ml) and water (9 ml) at 35° C. under nitrogen was added thionyl chloride (66.9 ml, 1.06 mol) dropwise After stirring at 35° C. overnight 300 ml was distilled off under vacuum and rediluted with toluene (250 ml) and water (10 ml) to give a solution of 5-chloromethyl-2-methyl-pyridine (J. Med. Chem, 2004, 47(11), 4787). The mixture was then heated to 40° C. and morpholine (112.2 ml, 1.29 mol) added and the slurry heated to 80° C. for 3 hrs. After cooling to room temperature saturated sodium carbonate solution (150 ml) was added and the aqueous phase separated and extracted with toluene (200 ml). The combined organic layer was washed with brine and concentrated. The oil was dissolved in iso-octane (300 ml) at 40° C. then cooled to −5° C. overnight. Two crops were obtained which gave 53.65 g, 72% yield of 4-[(6-methylpyridin-3-yl)methyl]morpholine as a beige solid. 1H NMR (400 MHz; CDCl3): δ 8.4 (d, J=1.72 Hz, 1H), 7.54 (dd, J=2.1, 7.91 Hz, 1H), 7.1 (d, J=7.92 Hz, 1H), 3.68 (apparent t, J=4.6, 9.28 Hz, 4H), 3.4 (s, 2H), 2.5 (s, 3H), 2.4 (apparent t, J=4.5, 8.93 Hz, 4H); 13C NMR: (100 MHz, CDCl3): δ 157.3, 149.8, 137.2, 129.9, 122.9, 66.9, 60.3, 53.5, 24.1 ppm; MS (ESI) m/z 193 [M+1]+; Melting point: 51-52° C.
Reaction SMILES: Cl.[CH:2]1([NH:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:23][C:24](Cl)=[O:25])[CH:20]([CH3:22])[CH3:21]>C(#N)C.O>[CH2:19]([O:23][C:24]([N:8]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[CH2:9][C:10]([OH:12])=[O:11])=[O:25])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)COC(=O)Cl
Reactant: O=C(O)CNC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)COC(=O)N(CC(=O)O)C1CCCCC1
Reaction time: 17 h
Yield: 93.6 %

Procedure:
To a solution of the commercially available cyclohexylglycine hydrochloride (15 g, 77.4 mmol) in acetonitrile (320 ml) and water (320 ml) was added potassium carbonate. Isobutylchloroformate (11.1 ml, 85.1 mmol) was added to the clear solution over 15 minutes and the reaction was stirred for 17 hours. The acetonitrile was removed under reduced pressure and the remaining aqueous layer was extracted twice with ether (100 ml). The aqueous layer was then acidified to pH 1 with 6N hydrochloric acid and extracted with dichloromethane (3×300 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to yield 18.64 g (94%) product as a white solid.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][CH:24]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[C:1]([N:9]1[CH2:10][CH2:11][CH:12]([C:15](=[O:17])[C:26]2[CH:25]=[CH:24][C:23]([F:22])=[CH:28][C:27]=2[F:29])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(F)c1
Reactant: O=C(O)C1CCN(C(=O)c2ccccc2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc(F)cc1F)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 1-benzoylpiperidine-4-carboxylic acid (66 g, 285 mmol) in dichloromethane (160 mL) was added thionyl chloride (26 mL, 388 mmol). After stirring at 60° C. for 1 h, the mixture was added portionwise to a stirred suspension of 2,4-difluorobenzene (45 g, 397 mmol) and anhydrous aluminum chloride (88 g, 666 mmol) in dichloromethane (245 mL), and the reaction mixture was refluxed for 5 h. The reaction mixture was poured into a mixture of ice and concentrated hydrochloric acid and extracted with chloroform. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. Recrystallization from hexane gave 1-benzoyl-4-(2,4-difluorobenzoyl)piperidine (46 g, 50%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:30]([F:33])([F:32])[F:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=1>>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]([C:30]([F:31])([F:32])[F:33])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(c1ccc(N)cc1)C(F)(F)F
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Product: CCOC(=O)C(c1ccc(Nc2cc(CC)nc(-c3cccc(Cl)c3)n2)cc1)C(F)(F)F
Yield: 98 %

Procedure:
Following General Procedure A1, 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.055 g, 0.22 mmol) was reacted with ethyl 2-(4-aminophenyl)-3,3,3-trifluoropropanoate (0.080 g, 0.33 mmol) to afford the title compound (0.100 g, 100%) as an amber oil. MW=463.88. 1H NMR (CDCl3, 300 MHz) δ 8.44-8.39 (m, 1H), 8.34-8.27 (m, 1H), 7.57-7.46 (m, 4H), 7.44-7.36 (m, 2H), 6.87 (s, 1H), 6.54 (s, 1H), 4.38-4.11 (m, 3H), 2.74 (q, J=7.6 Hz, 2H), 1.40-1.21 (m, 6H); APCI MS m/z 464 [M+H]+.
Reaction SMILES: CN(C)CCN(C)C.C([Li])(CC)C.C(=O)=O.CC(C)=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([F:29])[CH:23]=1.[Cl:30]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>O1CCCC1.CCCCCC.C1CCCCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([F:29])[C:23]=1[Cl:30]
Reactant: Cc1ccc(Cl)cc1F
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: O=C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1ccc(Cl)c(Cl)c1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
Under an argon atmosphere, to a solution (75 mL) of N,N,N′,N′-tetramethylethylenediamine (16.15 g) in dry tetrahydrofuran was added a solution (139 mL) of 1 mol/L-sec-butyllithium in hexane/cyclohexane under cooling (dry ice-acetone bath) at not higher than −60° C., and the mixture was stirred at the same temperature for 20 min. The mixture was further cooled to −78° C., and a solution (50 mL) of 4-chloro-2-fluoro-1-methylbenzene (18.26 g) in dry tetrahydrofuran was added thereto. After the reaction mixture was stirred at the same temperature for 30 min, a solution (275 mL) of hexachloroethane (119.6 g) in dry tetrahydrofuran was added dropwise thereto. The mixture was stirred at the same temperature for 30 min to gradually warm to room temperature. To the reaction mixture was added 6 mol/L hydrochloric acid to adjust to pH=5 and the mixture was concentrated. The residue was partitioned between ether and water, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was placed on a glass filter, washed with a small amount of ether and filtrated. The filtrate was concentrated and evaporated under reduced pressure. The fraction at the boiling point of 48° C. (1.5 Torr) was collected to give the title compound as a colorless oil (yield: 19 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[NH:14][C:13](=[O:18])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[K+].[CH3:21]I>O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:21])[C:13](=[O:18])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CI
Reactant: COc1ccc(-c2cc(=O)[nH]c(=O)[nH]2)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cc(=O)n(C)c(=O)[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 6-(3,4-dimethoxyphenyl)-2,4(1H,3H)-pyrimidinedione (1.0 g) in a mixture of water (5 ml) and methanol (5 ml) was added potassium hydroxide (0.57 g), and to an almost dissolved mixture was added methyl iodide (5 ml). The mixture was stirred at ambient temperature for 18 hours. The resulting precipitates were filtered and washed successively with water, ethanol and diisopropyl ether to afford 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (0.13 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[CH2:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH2:17]([O:19][C:20](=[O:24])[CH2:21][CH2:22][NH2:23])[CH3:18].O>C(N(CC)CC)C>[CH2:17]([O:19][C:20](=[O:24])[CH2:21][CH2:22][NH:23][CH2:15][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:18]
Reactant: CCOC(=O)CCN
Reactant: C=C(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNCC(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.4 %

Procedure:
To a solution of the compound (38.1 g) obtained in step 1 in triethylamine (20.4 mL) was added β-alanine ethyl ester monohydrochloride (22.5 g), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with diethyl ether. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure to give N-[2-(3,4-dichlorophenyl)-3-ethoxy-3-oxopropyl]-β-alanine ethyl ester (27.8 g, 78%) as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[CH2:11][C:10]2[CH:12]=[CH:13][C:14]([S:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:15][C:9]=2[CH:8]=[CH:7][C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]1=2)(=[O:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)Cl>[C:1]([N:4]1[CH2:11][C:10]2[CH:12]=[CH:13][C:14]([S:16]([CH2:17][CH2:18][CH2:19][CH3:20])=[O:33])=[CH:15][C:9]=2[CH:8]=[CH:7][C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CCCCSc1ccc2c(c1)C=Cc1ccccc1N(C(C)=O)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCS(=O)c1ccc2c(c1)C=Cc1ccccc1N(C(C)=O)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 135.8 %

Procedure:
To a solution of compound Example 287A (32 mg, 0.095 mmol) in CH2Cl2 (5 mL) at 0° C. was added mCPBA (13 mg, 0.05 mmol). The solution was stirred for 1 hour at 0° C. and for 1 hour at room temperature. The reaction was quenched by adding NaHCO3 solution. The aqueous layer was extracted with EtOAc (3×2 mL). The combined EtOAc extracts were washed with brine and dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 2:1 hexane/EtOAc) to give the title compound (24 mg, 77 %). HPLC Rt=3.7 min. m/z=354(M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O-:8])=[O:7])=[N:2]1.[ClH:9].[CH2:10](O)[CH3:11]>>[ClH:9].[NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH2:10][CH3:11])=[O:7])=[N:2]1
Reactant: O=C([O-])c1nc[nH]n1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1nc[nH]n1
Reaction time: 72 h
Yield: 48 %

Procedure:
1,2,4-Triazole-3-carboxylate (16 g) [G. I. Chipen and V. Ya. Grinshtein, Chem. Heterocyclic Compd. (U.S.S.R), 1,420 (1965)] dissolved in ethanol (400 ml) was saturated with HCl gas. Ice-bath cooling was applied to avoid overheating during saturation and the reaction was left stirring for three days. The product which had precipitated out was filtered off and washed with cold ethanol and then diethyl ether before being dried under vacuum giving 12 g of the product, 48% yield. νmax (Nujol Mull) 1754 cm-1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1([C:21](OCC)=[O:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.CCOCC>C1COCC1.C(Cl)(Cl)Cl>[F:7][C:8]1([CH2:21][OH:22])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]1
Reactant: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Temperature: 0 °C
Yield: 68.6 %

Procedure:
Lithium aluminium hydride (1M in THF) (2.36 mL, 2.361 mmol) was added dropwise to a stirred solution of 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (325 mg, 1.180 mmol) in THF (5.90 mL) cooled to 0° C. After 10 min ether (15 mL) was added and the reaction was quenched by sequential dropwise addition of water (0.1 mL), 10% NaOH (0.1 mL) and water (0.3 mL). The mixture was stirred at room temperature and the lithium salts that had precipitated were filtered off and washed with fresh ether. The organic filtrates were combined and solvent was removed in vacuo to leave a clear gum. The crude product was taken up in chloroform and loaded onto a 25+M Biotage silica column. Chromatography, eluting with a gradient of EtOAc in hexanes, gave tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (189 mg, 0.810 mmol, 69%) as a clear gum.
Reaction SMILES: Cl.[C:2]([CH:5]([C:13]1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:4])N.[CH3:24][OH:25]>>[Cl:19][C:18]1[C:13]([CH:5]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)[C:2]([O:25][CH3:24])=[O:4])=[N:14][CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: NC(=O)C(c1ccc(Cl)cc1)c1ncc(C(F)(F)F)cc1Cl
Reactant: CO
Agent: Cl
Product: COC(=O)C(c1ccc(Cl)cc1)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 16 h

Procedure:
Hydrogen chloride gas was introduced into a solution of 3.0 g of 2-[1-carbamoyl-1-(4-chlorophenyl)methyl]-3-chloro-5-trifluoromethylpyridine (prepared by the method of Example 3) in 100 ml of anhydrous methanol for 5 hours. The mixture was subsequently stirred for another 16 hours and excess hydrogen chloride was removed by passing nitrogen through the mixture. The methanol was separated off and the crude product was purified by silica gel chromatography (eluent: cyclohexane/tert-butyl methyl ether 50:1). Yield: 1.3 g (42%) of colorless crystals; mp.: 103-104° C.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:14]=[CH:13][C:12]2=[C:15]3[C:5]=1[O:6][CH2:7][C@H:8]([CH3:34])[N:9]3[C:10]([C@@H:16]([NH:18][C:19]1[N:27]=[CH:26][N:25]=[C:24]3[C:20]=1[N:21]=[CH:22][N:23]3C1CCCCO1)[CH3:17])=[N:11]2>O1CCOCC1.CO>[F:3][C:4]1[CH:14]=[CH:13][C:12]2=[C:15]3[C:5]=1[O:6][CH2:7][C@H:8]([CH3:34])[N:9]3[C:10]([C@@H:16]([NH:18][C:19]1[N:27]=[CH:26][N:25]=[C:24]3[C:20]=1[N:21]=[CH:22][NH:23]3)[CH3:17])=[N:11]2
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c3c2n1[C@@H](C)CO3
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c3c2n1[C@@H](C)CO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Hydrogen chloride HCl (340 μL of a 4M solution in dioxane) was added to a solution of [(S)-1-((S)-6-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethyl][9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (117 mg, 0.27 mmol) in MeOH (1 mL) and the reaction was stirred at RT for 30 min. The crude reaction mixture was passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo to give 441 (88 mg, 92%) as an off-white solid. LCMS (Method K): RT 2.61 min [M+H]+ 354.0. 1H NMR (CD3OD, 400 MHz): δ 8.23 (1H, s), 8.05 (1H, s), 7.08 (1H, dd, J=8.8, 3.1 Hz), 6.93 (1H, dd, J=12.1, 8.8 Hz), 5.77 (1H, br s), 5.19 (1H, qdd, J=6.7, 2.6, 1.8 Hz), 4.48 (1H, dd, J=11.5, 1.8 Hz), 4.20 (1H, dd, J=11.5, 2.6 Hz), 1.80 (3H, d, J=7.0 Hz), 1.47 (3H, d, J=6.7 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[C:18]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[N:19]=2)[C:14]([OH:16])=O)[CH3:9])=[CH:4][CH:3]=1.[CH:27]([NH:30]C(C)C)(C)[CH3:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.Cl.C(N)C>C(OCC)(=O)C.CN(C)C=O>[CH2:27]([NH:30][C:14](=[O:16])[C:13]1[CH:17]=[C:18]([NH:20][C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[N:19]=[C:11]([NH:10][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH3:9])[CH:12]=1)[CH3:28]
Reactant: C[C@H](Nc1cc(C(=O)O)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: CC(C)NC(C)C
Agent: CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=O)c1cc(Nc2cnccn2)nc(N[C@@H](C)c2ccc(F)cc2)c1
Reaction time: 48 h

Procedure:
To a dimethylformamide solution of 450 mg of (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinic acid (Example 141) and 2.2 ml of diisopropylamine was added, 1.32 g of 1H-benzotriazol-1-yloxy tripyrrolidinophosphonium hexafluorophosphate, and the mixture was stirred for 15 minutes. 520 mg of ethylamine hydrochloride was added thereto, and the mixture was stirred for 2 days. The reaction solution was diluted with ethyl acetate, and the organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off, and then the obtained residue was purified by silica gel column chromatography to obtain 390 mg of the objective compound as a pale yellow powder.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH:13]1([C:16](=[O:23])[CH2:17][C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])[CH2:15][CH2:14]1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[C:17]([C:16]([CH:13]2[CH2:15][CH2:14]2)=[O:23])[C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(CC(=O)C1CC1)C1CC1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: O=C(C(=Cc1cccc(C(F)(F)F)c1)C(=O)C1CC1)C1CC1

Procedure:
The procedure described in Example 19 was repeated by using 2.15 ml 3-trifluoromethylbenzaldehyde and 2.42 g 1,3-dicyclopropyl-1,3-propanedione. Yield 2.71 g, mp 56°-58° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([N:6]2[C:11](=[O:12])[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:28][CH2:29][CH3:30])[N:8]3[N:31]=[CH:32][N:33]=[C:7]23)[CH2:3]1.[N+](=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N-]>C([O-])(=O)C.[Rh+].C1(C)C=CC=CC=1>[CH2:40]([O:39][C:37](=[O:38])[CH2:36][O:1][C@H:2]1[CH2:5][C@@H:4]([N:6]2[C:11](=[O:12])[C:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]#[N:27])=[CH:18][CH:19]=3)=[C:9]([CH2:28][CH2:29][CH3:30])[N:8]3[N:31]=[CH:32][N:33]=[C:7]23)[CH2:3]1)[CH3:41]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@@H](O)C2)c2ncnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@@H](OCC(=O)OCC)C2)c2ncnn12
Reaction time: 1 h
Yield: 57 %

Procedure:
To a mixture of 4′-{[4-(cis-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.3 g), rhodium(I) acetate (0.003 g) and toluene (20 mL) was added dropwise ethyl diazoacetate (0.66 mL) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (0.2 g, 57%).