Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[C:10]([O:17][CH2:18][C:19]([O:21]CC)=O)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:3][CH2:2]1.[NH2:24][CH2:25][CH:26]([OH:38])[CH2:27][N:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29]1>CCO>[CH2:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:36][CH2:37][N:28]1[CH2:27][CH:26]([OH:38])[CH2:25][NH:24][C:19](=[O:21])[CH2:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[C:7]([N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[CH:16]=[CH:15]2
Reactant: CCOC(=O)COc1cccc2ccc(N3CCOCC3)nc12
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCO
Product: O=C(COc1cccc2ccc(N3CCOCC3)nc12)NCC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
To a stirred mixture of ethyl 2-((2-morpholinoquinolin-8-yl)oxy)acetate (100 mg, 0.316 mmol) in EtOH (2 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (65 mg, 0.316 mmol). The mixture was stirred at 120° C. for 0.5 hour under microwave conditions then after evaporation of solvent, the reaction mixture was purified by prep-HPLC to afford the title product (14 mg, Yield 10%). 1H NMR (400 MHz, MeOD) δ=8.04 (d, J=9.3 Hz, 1H), 7.43-7.36 (m, 1H), 7.23-7.16 (m, 3H), 7.10-7.00 (m, 3H), 6.97 (d, J=4.8 Hz, 1H), 4.77 (s, 2H), 3.96 (t, J=6.3 Hz, 1H), 3.87-3.83 (m, 4H), 3.77-3.72 (m, 4H), 3.63-3.53 (m, 2H), 3.52-3.45 (m, 1H), 3.40 (d, J=6.3 Hz, 1H), 2.83 (d, J=5.8 Hz, 2H), 2.75-2.67 (m, 2H), 2.56-2.37 (m, 2H). LCMS (m/z): 477.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1Cl>CN(C=O)C.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1cncc(Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2c(Cl)cncc2Cl)cc1
Temperature: 80 °C

Procedure:
To a vial containing 4-aminophenol (2.185 g, 20.0 mmol, 1 equiv.) in 60 mL DMF was added t-BuOK (2.468 g, 22.0 mmol, 1.1 equiv.) followed by 3,4,5-trichloropyridine (3.653 g, 20.0 mmol, 1 equiv.). The flask was fitted with a condenser and the mixture was stirred at 80° C. under nitrogen. After the reaction mixture was cooled, diluted with ethyl acetate (600 mL) and washed with water (3×150 mL) and brine. The organic layer was dried over Na2SO4, filtered and solvent was removed under vacuum. The crude material was absorbed onto silica gel and purified by flash column (7.5×12 cm silica) using 2500 mL 1:1 hexanes:ethyl acetate giving 4.6348 g (91%) of product as a light yellow crystalline solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][C:19]2[C:24]([C:25](=[O:27])[CH3:26])=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:15]=1.[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.CCCCCC>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][C:19]2[C:24]([C:25](=[O:27])[CH2:26][CH:30]([OH:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:28][CH:29]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cccnc1Oc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CC(O)c1ccccc1)c1cccnc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
A solution of 0.114 mL (111 mg, 1.10 mmol) of diisopropylamine in 8 mL of tetrahydrofuran was cooled to −78° C. and treated dropwise with 0.440 mL (1.10 mmol) of a solution of 2.5 M n-butyllithium in hexane. After stirring for 30 min, a solution of 231 mg (1.00 mmol) 1-[2-(4-Fluorophenoxy)-3-pyridinyl]-ethanone in 2 mL of tetrahydrofuran was added dropwise. After stirring for 30 min, 0.112 mL (1.07 mmol) of benzaldehyde was added dropwise, and stirring was continued for 1 h. The mixture was quenched by the addition of 2 mL of saturated aqueous NH4Cl solution and was allowed to warm to rt. The mixture was partitioned between 50 mL of saturated aqueous NH4Cl solution and 300 mL of EtOAc. The separated organic layer was washed with 50 mL of saturated aqueous sodium hydrogencarbonate solution, 50 mL of brine, dried (Na2SO4), and evaporated to 259 mg of an oil. Purification by flash chromatography using a 40% EtOAc-hexane eluant afforded 211 mg (63% yield) of the title compound as an oil; 1H NMR (CDCl3) d 3.23 (1H, br s), 3.54-3.56 (2H, m), 5.34-5.37 (1H, m), 7.07-7.41 (10H, m), 8.21-8.26 (2H, m); APCI MS (m/e) 338 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([OH:12])=[CH:7]2.[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH3:25])=[O:23])[CH:17]=1>CN(C=O)C.C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:12][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH3:25])=[O:23])[CH:17]=1)=[CH:7]2
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Nc1cccc2cc(O)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cc(Oc2ccc3c(N)cccc3c2)ccn1
Temperature: 90 °C

Procedure:
To a solution of 5-amino-2-napthol (2.8 g, 17.6 mmol) in DMF (20 mL), NaH (60% in oil, 843 mg, 21.1 mmol) was added and stirred until the bubbling stopped. To the mixture 4-chloro-N-methylpicolinamide (Org. Proc. Res. & Dev., 2002, 6, 777-781)(1 g, 5.86 mmol) was added and the reaction heated to 90° C. for 22 h. The mixture was cooled to RT and diluted with CHCl3 and washed with water. The emulsion was filtered thru a pad of Celite and the layers separated. The water was washed with CHCl3 and the organic portions combined and washed with 1N NaOH and brine, dried with Na2SO4, filtered and evaporated. The residue was purified by column chromatography using hexanes and EtOAc as the eluent to give the title compound as a rose-colored solid.
Reaction SMILES: S([C:5]1[N:6]=[C:7]2[N:11]([C:12]=1C(OCC)=O)[CH:10]=[CH:9][S:8]2)(C)(=O)=O.[CH:18]([SH:21])([CH3:20])[CH3:19]>>[CH:18]([S:21][C:5]1[N:6]=[C:7]2[N:11]([CH:12]=1)[CH:10]=[CH:9][S:8]2)([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1c(S(C)(=O)=O)nc2sccn12
Reactant: CC(C)S
Product: CC(C)Sc1cn2ccsc2n1

Procedure:
In a manner similar to the procedure in Reference Example 1, the oily title compound was prepared from ethyl 6-mesylimidazo[2,1-b]thiazole-5-carboxlate and isopropyl mercaptan. ##STR10##
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.N1C=CC=CC=1.[CH2:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[CH2:23]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:10]2[CH2:9][CH2:8][CH:7]([N:6]3[C:5]4[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=4[NH:3][C:2]3=[O:1])[CH2:12][CH2:11]2)=[O:32])=[CH:34][CH:35]=1)[CH2:24][CH2:25][CH3:26]
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1ccc(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 4-(2-keto-1-benzimidazolinyl)piperidine (0.34 g, 1.57 mmol) in methylene chloride (8 mL) was added pyridine (0.15 mL, 1.88 mmol) and 4-n-butylbenzoyl chloride (0.37 g, 1.88 mmol). The reaction mixture was stirred for 1 h then purified directly by column chromatography on silica gel by eluting with methylene chloride followed by ethyl acetate. The product fractions were combined and concentrated in vacuo. The residue was triturated with ethyl ether and the solids collected by filtration and rinsed with hexanes. 1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (0.48 g; 81%) was obtained as white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>CCOC(C)=O>[OH:17][CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: OCCc1cccc(B(O)O)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(CCO)c3)nc12

Procedure:
1-{2-[3-(2-Hydroxy-ethyl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-(2-hydroxyethyl)benzeneboronic acid following general procedures as described in these Examples. Silica gel chromatography using 20-100% EtOAc in hexanes as eluant provided 69 mg (41%) of a yellow solid. MP 202-203° C., M+H=324.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][C:8]([N:11]=[N+:12]=[N-:13])([CH3:10])[CH3:9])(=[O:4])=[O:3].[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][CH2:15]2>CC(=O)CCC>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[N:11]([C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][N+:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][CH2:15]2)=[N+:12]=[N-:13]
Reactant: CC(C)(CCOS(C)(=O)=O)N=[N+]=[N-]
Reactant: C1CN2CCC1CC2
Solvent: CCCC(C)=O
Product: CC(C)(CC[N+]12CCC(CC1)CC2)N=[N+]=[N-]
Product: CS(=O)(=O)[O-]

Procedure:
In a 1 dram vial, a solution of 3-azido-3-methylbutyl methanesulfonate (0.45 g, 2.19 mmol) and quinuclidine (0.21 g, 1.9 mmol) in 2-pentanone (2.0 mL) was heated on a heat block at 110° C. for 16 h. The suspension was cooled, filtered, and rinsed with diethyl ether (50 mL). The filtrate was discarded and the solid was dried under high vacuum to give a white solid. (052 g, 74.7%). 1H NMR (D2O, 400 MHz): δ 1.35 (s, 6H), 1.95-2.05 (m, 8H), 2.18-2.22 (pent, J=3.6, 1H), 2.82 (s, 3H), 3.24-3.30 (m, 2H), 3.38-3.45 (m, 6H). LRMS (ESI+) for C12H23N4+(223.2); Found: 223 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:9]2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=2)[CH2:30][CH2:29]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCCc1cc(CCC=O)n(-c2ccc(C)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(C)cc2)n1

Procedure:
297 mg (70.6%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-methylphenyl)-3-butyl-1H-pyrazol-5-yl)propanal (248 mg, 0.968 mmol), 1-(2-fluorophenyl)piperazine (229 mL, 1.451 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[NH2:20][C:21]1[C:22]([C:33]#[N:34])=[N:23][CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:26]=1.Cl.O1CCOCC1>CN1C(=O)CCC1>[F:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH:20][C:21]1[C:22]([C:33]#[N:34])=[N:23][CH:24]=[C:25]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[CH:26]=1)=[C:3]([CH3:19])[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[N:5]2
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Reactant: N#Cc1ncc(N2CCOCC2)cc1N
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Nc1cc(N2CCOCC2)cnc1C#N

Procedure:
Prepared according to general Procedure K using 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (93 mg, 0.34 mmol), 3-amino-5-morpholinopicolinonitrile (70 mg, 0.34 mmol) and a 4.0M solution of HCl in dioxane (0.08 mL, 0.34 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 3-((5-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)-2-pyridinecarbonitrile was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.68 (1H, dt, J=3.1, 1.6 Hz), 8.00 (1H, d, J=8.6 Hz), 7.87-7.97 (3H, m), 7.64 (1H, td, J=8.2, 5.5 Hz), 7.39 (1H, ddd, J=7.0, 4.9, 1.8 Hz), 7.17-7.32 (2H, m), 6.23 (1H, d, J=2.3 Hz), 3.75-3.86 (4H, m), 3.17-3.31 (4H, m), 2.29 (3H, s). Mass Spectrum (ESI) m/e=441.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[Cl:7].[CH3:8][N:9]1[C:13]([C:14](Cl)=[O:15])=[C:12]([CH3:17])[CH:11]=[C:10]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl[Sn](Cl)(Cl)Cl.Cl>C(Cl)Cl>[CH3:8][N:9]1[C:13]([C:14]([C:6]2[N:2]([CH3:1])[C:3]([Cl:7])=[CH:4][CH:5]=2)=[O:15])=[C:12]([CH3:17])[CH:11]=[C:10]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)Cl)n1C
Reactant: Cn1cccc1Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)n2C)n1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
1-Methyl-2-chloropyrrole (5.83 g, 0.05 mole) and ethyl 1,4-dimethyl-5-chlorocarbonylpyrrole-2-acetate (11.5 g, 0.05 mole) are dissolved in 25 ml methylene chloride and stirred under nitrogen atmosphere at 0° C. Thirteen grams (0.05 mole) of SnCl4 in 10 ml methylene chloride is added slowly to the vigorously stirred solution. The resulting orange-brown mixture is stirred at 0° C. for 30 minutes then at room temp. for 3 hours. At the end of this period, 20 ml of 6 N HCl is added and stirred for 30 minutes. The mixture is extracted three times with 100 ml portions of methylene chloride and the crude product is purified by column chromatography and recrystallized from ether/petroleum ether to afford 9.5 g (63% yield) of ethyl 1,4-dimethyl-5-(1-methyl-5'-chloropyrrol-2-oyl)pyrrole-2-acetate.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH2:11])[CH:3]=1.[Cl:12][C:13]1[N:18]2[N:19]=[C:20]([CH3:22])[CH:21]=[C:17]2[N:16]=[C:15]([NH2:23])[CH:14]=1.[C:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>N1C=CC=CC=1>[C:24]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:11][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:33])=[CH:35][CH:36]=1)([CH3:27])([CH3:25])[CH3:26].[C:24]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:23][C:15]2[CH:14]=[C:13]([Cl:12])[N:18]3[N:19]=[C:20]([CH3:22])[CH:21]=[C:17]3[N:16]=2)=[O:33])=[CH:35][CH:36]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cc(Cl)n2nccc2n1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)C)cc3)cc(Cl)n2n1
Reaction time: 2 h
Yield: 47 %

Procedure:
7-Chloropyrazolo[1,5-a]pyrimidin-5-amine 1E (1.0 equivalent) or 7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J, 1.0 equivalent) was dissolved in anhydrous pyridine (0.35 M). 4-t-Butylbenzoic acid chloride (1.05 equivalents) was added at 0° C., and the mixture was stirred for two hours. The reaction was then quenched with saturated NaHCO3; pyridine was removed in vacuo and the residue was extracted with EtOAc. Combined organic layers were washed twice with 0.2 N HCl to remove residual pyridine, dried over MgSO4, filtered and concentrated. Crude product was purified by column chromatography (SiO2, gradient of 15 to 30% EtOAc/hexanes). The purified product was triturated with Et2O to give 4-tert-butyl-N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)benzamide (1F, 47%) or 4-tert-butyl-N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)benzamide (1K) of the product as a solid.
Reaction SMILES: [NH:1]1[CH2:6]CCC[CH2:2]1.[C:7](O)(C(F)(F)F)=O.[NH:14]1[CH:18]=[C:17]([CH:19]=[O:20])[N:16]=[N:15]1>CC(O)C.O>[CH3:2][N:1]([CH2:6][C:18]1[C:17]([CH:19]=[O:20])=[N:16][NH:15][N:14]=1)[CH3:7]
Reactant: C1CCNCC1
Reactant: O=C(O)C(F)(F)F
Reactant: O=Cc1c[nH]nn1
Solvent: O
Solvent: CC(C)O
Product: CN(C)Cc1n[nH]nc1C=O
Temperature: 22.5 °C

Procedure:
The piperidine adduct (62.1 g, 87 wt %, 54.0 g assay, 0.117 mol) was slurried in IPA/water (98:2, 365 mL). TFA (26.7 g, 18.0 mL, 0.234 mol) was added over 10 minutes maintaining the temperature at 20-25° C. The triazole aldehyde was liberated during the pH adjustment. The product crystallized from the reaction mixture.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[Br:15][CH2:16][C:17](Br)=[O:18]>C(Cl)(Cl)Cl>[Br:15][CH2:16][C:17]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: CSc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CSc1ccc(NC(=O)CBr)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-(methylthio)aniline (200 mg, 1.44 mmol) in chloroform (2 ml), a saturated aqueous solution of sodium hydrogencarbonate (2 ml) was added, followed by the dropwise addition of a solution of bromoacetyl bromide (300 mg, 1.49 mmol) in chloroform (2 ml) under ice cooling. The mixture was then stirred for 1 hour. The chloroform layer was separated, washed successively with 2N hydrochloric acid (10 ml) and brine (10 ml), and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, whereby the title compound (356 mg, 95.3%) was obtained as pale brown crystals.
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]2[C:3]=1[C:4]([OH:22])=[C:5]1[C:10](=[C:11]2[OH:19])[C:9](=[O:20])[CH2:8][CH2:7][C:6]1=[O:21].[F:23][C:24]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]2[C:25]=1[C:26](=[O:37])[O:27][C:28]2=O>>[F:1][C:2]1[C:3]2[C:12](=[C:11]([OH:19])[C:10]3[C:9](=[O:20])[C:8]4[C:7]([C:6](=[O:21])[C:5]=3[C:4]=2[OH:22])=[C:28]([OH:27])[C:29]2[C:25](=[C:24]([F:23])[C:32]([F:33])=[C:31]([F:34])[C:30]=2[F:35])[C:26]=4[OH:37])[C:13]([F:18])=[C:14]([F:17])[C:15]=1[F:16]
Reactant: O=C1CCC(=O)c2c1c(O)c1c(F)c(F)c(F)c(F)c1c2O
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Product: O=C1c2c(c(O)c3c(F)c(F)c(F)c(F)c3c2O)C(=O)c2c1c(O)c1c(F)c(F)c(F)c(F)c1c2O

Procedure:
{1-1} First, 1,2,3,4,8,9,10,11-octafluoro-5,7,12,14-tetrahydroxypentacene-6,13-dione (3) was synthesized from 5,6,7,8-tetrafluoro-9,10-dihydroxy-2,3-dihydroanthracene-1,4-dione (1) and 4,5,6,7-tetrafluoroisobenzofuran-1,3-dione (2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26](C)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:30])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CC(C)CCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Product: CC(C)CCc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 366) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.0756 g, 16%). mp 167–170° C. 1H NMR (300 MHz, DMSO d6) δ 0.78 (d, J=6 Hz, 6H), 1.47 (5H, obstructed by hexanes), 7.51–7.65 (m, 4H), 7.68 (m, 2H), 7.75 (m, 1H), 7.98 (m, 2H), 8.03 (s, 1H), 8.60 (bs, 1H). MS (DCI/NH3) m/z 432 (M+H)+, 449 (M+NH4)+. Anal. calc. for C21H22ClN3O3S (0.25 H2O): C, 57.79; H, 5.19; N, 9.62. Found: C, 57.78; H, 5.02; N, 9.40.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[S:14][CH:15]=1.FC(F)(F)C1SC=C([C:27]2C=CC=C[C:28]=2[OH:33])N=1.BrCCBr.C(#[N:42])C>>[F:17][C:16]([F:19])([F:18])[C:13]1[S:14][CH:15]=[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2][NH:42][CH2:27][CH2:28][OH:33])[N:12]=1
Reactant: CC#N
Reactant: FC(F)(F)c1nc(-c2ccccc2OCCBr)cs1
Reactant: Oc1ccccc1-c1csc(C(F)(F)F)n1
Solvent: BrCCBr
Product: OCCNCCOc1ccccc1-c1csc(C(F)(F)F)n1
Temperature: 70 °C

Procedure:
Synthesis of 4-[2-(2-bromoethoxy)phenyl]-2-(trifluoromethyl)-1,3-thiazole (C5) Cesium carbonate (266 mg, 0.816 mmol) was added to a solution of 2-[2-(trifluoromethyl)-1,3-thiazol-4-yl]phenol (C4) (100 mg, 0.408 mmol) and 1,2-dibromoethane (0.35 mL, 4.1 mmol) in acetonitrile (33 mL), and the mixture was heated at 70° C. for 18 hours. After cooling to room temperature, the reaction was partitioned between dichloromethane and water; the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 10% to 30% ethyl acetate in heptane) afforded the title compound. Yield: 115 mg, 0.327 mmol, 80%. 1H NMR (400 MHz, CDCl3) δ 3.78 (br dd, J=5.5, 5.5 Hz, 2H), 4.48 (dd, J=5.7, 5.5 Hz, 2H), 6.97 (br d, J=8.4 Hz, 1H), 7.13 (ddd, J=7.7, 7.4, 1.1 Hz, 1H), 7.35 (ddd, J=8.3, 7.3, 1.8 Hz, 1H), 8.31 (dd, J=7.8, 1.8 Hz, 1H), 8.37 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C1([SiH3])C=CC=CC=1>C1COCC1>[N:15]1([C:18]2[CH:19]=[CH:20][C:21]([NH:22][CH2:1][C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)=[CH:23][CH:24]=2)[CH2:14][CH2:13][O:12][CH2:17][CH2:16]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CNc2ccc(N3CCOCC3)cc2)cc1

Procedure:
A suspension of 4-formylbenzoic acid (2.53g; 16.8 mmol; 1 eq), 4-morpholinoaniline (3g; 16.8 mmol; 1 eq) and BU2SnCl2 (510 mg; 1.68 mmol; 0.1 eq) in dry THF (20 ml) was treated with PhSiH3 (3.31 ml; 16.8 mmol; 1 eq) at room temperature for 12 h. The reaction was filtered and the solid product was washed with MeOH. The yield of the reaction was 5.25g (99%). LRMS: calc 312.37; found: 313.2.