Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C:6]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Br:22])[CH:18]=2)[N:13]=1)([CH3:11])[C:7]([F:10])([F:9])[F:8])(=O)=O.[CH3:23][Al](C)C>C1CCCCC1>[Br:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:6]([CH3:23])([CH3:11])[C:7]([F:10])([F:9])[F:8])[CH:21]=[CH:20]2
Reactant: CC(OS(C)(=O)=O)(c1ccc2cc(Br)ccc2n1)C(F)(F)F
Reactant: C[Al](C)C
Solvent: C1CCCCC1
Product: CC(C)(c1ccc2cc(Br)ccc2n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A suspension of 6-bromoquinolin-2-yl-2,2,2-trifluoro-1-methylethyl methanesulfonate (11.97 g, 30 mmol) in cyclohexane (120 ml) was added trimethylaluminum (120 ml, 123 mmol, 1.03M in hexane solution) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction was carefully quenched with saturated sodium bicarbonate aqueous solution (30 ml), brine (10 ml) and diluted with ethyl acetate and heptane (200 ml). After the mixture was stirred for 30 minutes, formed precipitate was removed by celite and washed with ethyl acetate. The filtrate was concentrated and purified through silica gel column chromatography eluting with hexane only to furnish the title compound (9.56 g, 80% yield) as colorless oil. 1H NMR (300 MHz, CDCl3) ppm 1.72 (6H, s), 7.66 (1H, d, J=8.8 Hz), 7.75-7.80 (1H, m), 7.96-8.00 (2H, m), 8.06 (1H, d, J=8.8 Hz). MS (ESI): m/z 318, 320 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C>>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([B:18]([OH:23])[OH:19])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCN(CC)c1ccc(Br)cc1
Agent: [Li]CCCC
Product: CCN(CC)c1ccc(B(O)O)cc1
Yield: 94.6 %

Procedure:
In a manner similar to that of Example 1c, by reacting 5 g of (4-bromo-phenyl)diethylamine (21.9 mmol) with 13 mL of 2.0 M n-butyllithium solution and 6 mL (26 mmol) of triisopropyl borate. 4 g of 4-diethylaminophenylboronic acid (yield=94%) are obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16](Br)=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH:30]2[CH2:31][CH2:32][CH:26]1[CH:27]=[C:28](B1OC(C)(C)C(C)(C)O1)[CH2:29]2)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([O:22][C:23]([N:25]1[CH:30]2[CH2:31][CH2:32][CH:26]1[CH:27]=[C:28]([C:16]1[CH:15]=[CH:14][CH:13]=[C:10]([C:11]#[N:12])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:29]2)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1C2C=C(B3OC(C)(C)C(C)(C)O3)CC1CC2
Reactant: N#Cc1cccc(Br)c1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C2C=C(c3cccc(C#N)c3OCc3ccccc3)CC1CC2
Temperature: 25 °C
Yield: 64.5 %

Procedure:
To a flask was added 2-benzyloxy-3-bromobenzonitrile (1.29 g, 4.47 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (1.50 g, 4.47 mmol), and THF (30 mL), 2.0 M sodium carbonate in water (8.95 mL), and bis(triphenylphosphine)palladium(II) chloride (78 mg, 0.11 mmol). The reaction mixture was purged with nitrogen, heated to reflux overnight, cooled to room temperature, and concentrated. The resulting solution was diluted with DCM (25 mL) and washed with water (25 mL) The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with ethyl acetate in hexanes (0-50%) to give partially purified product (1.2 g). (m/z): [M+H]+ calcd for C26H28N2O3 416.21. (-tert-butyl 361.2); found 361; (-Boc 317.2); found 317.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=[C:31]([NH2:44])[N:30]=1>>[CH3:28][C:29]1[C:34]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:33][N:32]=[C:31]([NH2:44])[N:30]=1
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (225 mg) was coupled to 4-methyl-5-(4,4,5,5-tetramethyl (1,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine via General Procedure A to yield 42 mg of 379. MS (Q1) 505.2 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(-c2cnc3[nH]ccc3c2N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
tert-Butyl 4-(5-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazine-1-carboxylate (0.111 g, 0.272 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 2 hours. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give 5-(3-methoxyphenyl)-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyri dine (0.083 g, 99% yield) as the dihydrochloride salt.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.Cl.[NH2:14][C:15]([NH2:17])=[NH:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[CH:4]=[CH:3][N:14]=[C:15]([NH2:17])[N:16]=1
Reactant: CN(C)C=CC(=O)c1ccco1
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nccc(-c2ccco2)n1
Temperature: 100 °C
Reaction time: 21 h
Yield: 85.8 %

Procedure:
A suspension of 3-(dimethylamino)-1-(2-furyl)-2-propen-1-one (5.0 g, 30.3 mmol), guanidine hydrochloride (5.8 g, 60.7 mmol) and potassium carbonate (8.4 g, 60.9 mmol) in N,N-dimethylformamide (50 ml) was stirred at 100° C. for 21 hours. After cooling as it was, the reaction mixture was diluted with ice water (250 ml). The resulting solid was collected by filtration and washed with water, to give the title compound (4.19 g, 86%) as a pale brown solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([OH:23])[CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])C.[CH3:25][NH2:26]>C(O)C>[CH3:25][NH:26][C:4](=[O:3])[CH:5]([OH:23])[CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: CN
Reactant: CCOC(=O)C(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Solvent: CCO
Product: CNC(=O)C(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Yield: 94.2 %

Procedure:
40 g of ethyl-2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propionate in 1 liter of 95° ethyl alcohol and 250 ml of 35% methylamine was heated in a stopped vessel at 40°-50° C. for 24 hours. The whole was evaporated to dryness under vacuum, taken up with 200 ml of absolute ethyl alcohol, again evaporated to dryness and the residue crystallized from isopropanol. There was in this way obtained 36 g (94.2%) of N-methyl-2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propionamide, melting point 162°-163° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Reactant: Clc1cccnc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3ncccc3Cl)CC2)cc1
Yield: 28.3 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was reacted with 2,3-dichloropyridine (108 mg, 0.72 mmol), DIEA (0.25 ml, 1.44) and 1,4-dioxane (0.3 ml) at 185° C. to afford the title compound (40 mg), a white solid, in 28% yield.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]=2[C:18]([OH:20])=O)=[CH:4][CH:3]=1.Cl.[NH2:22][CH:23]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:24]1=[O:25]>N1C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:11]3[C:10]=2[C:18](=[O:20])[N:22]([CH:23]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:24]2=[O:25])[C:12]3=[O:14])=[CH:4][CH:3]=1
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(OCc2ccc(Cl)s2)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccc(Cl)s4)c3C2=O)C(=O)N1
Yield: 36.8 %

Procedure:
A mixture of 3-(5-chloro-thiophen-2-ylmethoxy)-phthalic acid (1.6 g, 5.1 mmol), alpha-amino-glutarimide hydrochloride (0.88 g, 5.4 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(5-chloro-thiophen-2-ylmethoxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (0.76 g, 36% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 2.63 min (99.3%); mp, 217-219° C.; 1H NMR (DMSO-d6) δ 2.01-2.07 (m, 1H, CHH), 2.54-2.57 (m, 2H, CH2), 2.62-2.95 (m, 1H, CHH), 5.10 (dd, J=6, 12 Hz, 1H, CH), 5.50 (s, 2H, CH2), 7.07-7.87 (m, 5H, Ar), 11.11 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.93, 30.90, 48.75, 65.38, 115.94, 116.80, 120.44, 126.55, 127.83, 129.09, 133.31, 136.93, 137.54, 154.76, 165.14, 166.68, 169.77, 169.86, 172.73. Anal Calcd For C18H13N2O5SCl: C, 53.41; H, 3.24; N, 6.92; S, 7.92%; Cl, 8.76. Found: C, 53.39; H, 2.95; N, 6.80; S, 7.62%; Cl, 9.01.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:29]3[CH2:30][CH2:31][N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][CH2:28]3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)N=C(N1CCN(c3ccccc3)CC1)c1cccc3c1N2CC3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
A stirred mixture of 7.88 g (0.0250 mole) of 9-bromo-1,2dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-one and 1200 ml of toluene was heated under nitrogen until a solution resulted. Then there was added 40.6 g (0.250 mole) of N-phenylpiperazine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was heated under reflux for three hours, cooled to room temperature and treated with 500 ml of 2N sodium hydroxide solution. After stirring vigorously for 15 minutes, the layers were separated. The aqueous phase was extracted with 300 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, and concentrated to an oil. The oil was taken up in 80 ml of hot methanol, from which the product crystallized, affording 7.8 g (68%) of product. Recrystallization from a hot solution of dichloromethane (25 ml) to which methanol (25 ml) was added, provided the analytical sample, mp 171°-173° C.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH:5]=[C:6]([CH3:8])[CH3:7])[CH3:3].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12]>>[C:9]([C:10]1[C:2]([CH3:3])([CH3:1])[CH:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[O:12][C:11]=1[CH3:13])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)=CC=C(C)C
Product: CCOC(=O)C1=C(C)OC(CC(C)C)C1(C)C

Procedure:
2,5-Dimethyl-2,4-hexadiene and ethyl acetoacetate were reacted utilizing the oxidative addition procedure to obtain 4-carbethoxy-2-(2-methyl-1-propenyl)-3,3,5-trimethyl-2,3-dihydrofuran. Manganese (III) acetate obtained by the reaction potassium permanganate (19.75 grams) and manganese (II) acetate (122.5 grams) in 250 mls acetic acid was employed for the oxidation. The 2,5-dimethyl-2,4-hexadiene (27.5 gram) and ethyl acetoacetate (32.5 grams) were reacted in the presence of 0.5 grams cupric acetate catalyst. 4Carbethoxy-2-(2-methyl-1-propenyl)-3,3,5-trimethyl-2,3-dihydrofuran was recovered (61% yield) and hydrogenated in ethanol using a supported palladium catalyst (5% Pd on carbon) to obtain 4-carbethoxy-2-(2-methylpropyl)-3,3,5-trimethyl-2,3-dihydrofuran. Essentially pure (97+%) 4-carbethoxy-2-(2-methylpropyl)-3,3,5-trimethyl-2,3-dihydrofuran (B.P. 136° C. @9.2 mm Hg; nD23° 1.4642) was obtained upon distillation of the crude product. The product had a green vegetable odor. The structure of the product ##STR23## was confirmed by infrared and nuclear magnetic resonance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]>[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[CH2:14][CH2:15]2)[OH:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: COc1ccccc1OCCCCl
Agent: [I-]
Agent: [K+]
Product: COc1ccccc1OCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 66 %

Procedure:
Following the procedure of Example 1, [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and 1-chloro-3-(2-methoxyphenoxy)propane were reacted using in addition potassium iodide catalyst to give the title compound in 66% yield, (recrystallizing from isopropyl alcohol), m.p. 127°-218° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:33])[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([NH:24][NH2:25])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(=O)(O)[O-].[Na+].Br[C:40]#[N:41]>O1CCOCC1.O>[NH2:41][C:40]1[O:23][C:22]([C:21]2[C:20]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[CH:19][C:18]([CH2:31][CH3:32])=[C:17]([CH:26]=2)[C:15]([N:12]2[CH2:11][CH2:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)([F:33])[CH2:14][CH2:13]2)=[O:16])=[N:24][N:25]=1
Reactant: CCc1cc(C2CCC2)c(C(=O)NN)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(C2CCC2)c(-c2nnc(N)o2)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a round-bottom flask was added a solution of 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazide (compound 217.2, 450 mg, 1.00 mmol, 1.00 equiv) in 1,4-dioxane (10 mL). A solution of sodium bicarbonate (252 mg, 3.00 mmol, 2.99 equiv) in water (10 mL) and BrCN (128 mg, 1.21 mmol, 1.20 equiv) were added to the reaction mixture. The resulting solution was stirred for 3 h at room temperature, then quenched with 30 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This resulted in 400 mg (84%) of 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]2)=[N:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1.O>C(#N)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[N:6][C:7]=1[Br:21]
Reactant: Nc1cnc([C@@H]2CC[C@H](O)C2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: Nc1ncc([C@@H]2CC[C@@H](O)C2)nc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N,N-Di-tert-butyl (5-((1R,3S)-3-hydroxycyclopentyl)pyrazin-2-yl)carbamate (35 mg, 0.092 mmol) in DCM (461 μl) was added HCl (922 μl, 3.69 mmol), the reaction mixture was stirred at room temperature overnight and concentrated to dryness yielding HCl salt. The crude product was used in next step reaction without purification. LCMS (m/z): 180.1 (MH+), 0.22 min. (+/−)-(1S,3R)-3-(5-aminopyrazin-2-yl)cyclopentanol (15 mg, 0.084 mmol) was dissolved in acetonitrile (2 mL), then NBS (16.39 mg, 0.092 mmol) was added, the reaction mixture was stirred at room temperature for 30 min, water was added, the reaction mixture was then extracted by EtOAc, the organic was dried and concentrated, the crude material was used in next step reaction. LCMS (m/z): 258.1/260.2 (MH+), 0.45 min. Following the above method, using (+/−)-N,N-Di-tert-butyl (5-((1R,3S)-3-hydroxycyclopentyl)pyrazin-2-yl)carbamate, (+/−)-(1R,3R)-3-(5-amino-6-bromopyrazin-2-yl)cyclopentanol was obtained. LCMS (m/z): 258.1/260.1 (MH+), 0.50 min.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: NCc1ccc(Cl)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1ccc(CNc2nc(Cl)nc3nc[nH]c23)cc1
Temperature: 80 °C

Procedure:
To a suspension of 15 g (0.0794 mol) of 2,6-dichloropurine in 250 mL of absolute ethanol was added 12.7 mL (0.0873 mol) of triethylamine and 10.62 mL (0.0873 mol) of 4-chlorobenzylamine. The mixture was refluxed at 80° C. for 16 h (the formation of creamy white precipitate was observed). The reaction mixture was cooled and the precipitated product was removed by filtration. The precipitate was washed with ethanol (350 mL) and dried in high vacuum for 24 h. Product was characterized by 1H-NMR.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([O:12][CH3:13])=[N:10][CH:9]=[CH:8][N:7]3[C:14]=2I)[CH2:3][CH2:2]1.[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]>>[CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([O:12][CH3:13])=[N:10][CH:9]=[CH:8][N:7]3[C:14]=2[CH:35]([OH:36])[C:33]2[CH:32]=[CH:31][C:25]3/[C:26](=[C:27](/[CH3:30])\[C:28]#[N:29])/[C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:37][C:21]=4[O:22][CH2:23][C:24]=3[CH:34]=2)[CH2:3][CH2:2]1
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: COc1nccn2c(I)c(C3CC3)nc12
Product: COc1nccn2c(C(O)c3ccc4c(c3)COc3cc(F)ccc3/C4=C(\C)C#N)c(C3CC3)nc12
Yield: 104.8 %

Procedure:
[step 3] Using 2-cyclopropyl-3-iodo-8-methoxyimidazo[1,2-a]pyrazine (9.2 g, 29 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (5.3 g, 18 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 14A, step 3, (E)-2-{8-[(2-cyclopropyl-8-methoxyimidazo[1,2-a]pyrazin-3-yl)(hydroxy)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (9.1 g, quantitative) was obtained.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[C:11]([CH3:19])[N:10]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH2:32])[CH:21]=1>CN(C=O)C>[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH:12]=[C:11]([CH3:19])[N:10]=1
Reactant: NCCOCCCc1cccnc1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(NCCOCCCc2cccnc2)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.6 %

Procedure:
Under a nitrogen atmosphere, triethylamine (6.1 mL, 44 mmol) was added to a solution of 2,4-dichloro-6-methyl-3-nitropyridine (7.50 g, 36.2 mmol), prepared as described in Part A of Example 1, in anhydrous DMF (160 mL). Neat 2-[3-(pyridin-3-yl)propoxy]ethylamine (6.60 g, 36.6 mmol) was then added, and the mixture was stirred at room temperature for 1.5 hours. The volatiles were then removed under reduced pressure, and the residue was dissolved in chloroform. The solution was washed with 2% aqueous potassium bicarbonate (1×), water (1×), and brine (1×), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide an oil. The crude product was purified by column chromatography on silica gel (600 g, eluting with methanol:ethyl acetate in various ratios) to afford an oil which was dried under reduced pressure to yield 4.9 g of (2-chloro-6-methyl-3-nitropyridin-4-yl)-{2-[3-(pyridin-3-yl)propoxy]ethyl}amine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:31][CH2:32][N:33]([C:11]([C:9]3[S:10][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:14][C:7]=4[CH:8]=3)=[O:13])[CH2:34][CH2:35]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: N#Cc1ccc2sc(C(=O)O)cc2c1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: N#Cc1ccc2sc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2c1

Procedure:
In the same manner as in Referential Example 319, a reaction was effected using 5-cyanobenzothiophene-2-carboxylic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][N:8]1[CH2:14][CH:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:12]2[CH:26]=[CH:27][CH:28]=[CH:29][C:11]=2[CH2:10][CH2:9]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:5]([O:4][C:2](=[O:3])[NH:7][N:8]1[CH2:14][CH:13]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=2)[C:12]2[CH:26]=[CH:27][CH:28]=[CH:29][C:11]=2[CH2:10][CH2:9]1)[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: NN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)NN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of ethyl chloroformate (3.6 g) in 25 ml dichloromethane was slowly added to a solution of 3-amino-2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepine (9 g) in 100 ml dichloromethane containing sodium bicarbonate (7 g). After one hour, the reaction mixture was filtered and concentrated to 11 g solid. A 3 g sample was recrystallized from ether to yield 2.2 g white crystals, mp 156°-157°.