Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[H-].[Na+].Cl[CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24]>C1COCC1>[Cl:1][C:2]1[C:3]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:5]2[N:9]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: COCCOCCl
Reactant: Clc1cc2[nH]cnc2cc1N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCn1cnc2cc(Cl)c(N3CCCC3)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6-chloro-5-pyrrolidin-1-yl-1H-benzoimidazole (0.443 g, 2.00 mmol) and THF (5 mL) was added NaH (96.0 mg, 60% dispersion in mineral oil, 2.40 mmol) at 0° C. After stirring the reaction mixture for 30 min at 0° C., 1-chloromethoxy-2-methoxy-ethane (0.299 g, 2.40 mmol) was added and the mixture was stirred for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×20 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (0-10% MeOH/DCM) to yield the titled compound as a mixture of regioisomers (0.240 g, 39%) with a purity of 90%. MS (ESI/CI): mass calcd. for C15H20ClN3O2, 309.1; m/z found, 310.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](Cl)(=[O:12])[CH:10]=[CH2:11]>>[C:9]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)(=[O:12])[CH:10]=[CH2:11]
Reactant: Oc1ccc(O)cc1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)Oc1ccc(O)cc1

Procedure:
Compound 5 can be prepared, for example, by the following method. Namely, hydroquinone and acrylic acid chloride are reacted to obtain 4-hydroxyphenyl acrylate (Formula 6) as a half ester. On the other hand, a 4-alkoxycarbonyloxy benzoic acid is heated and refluxed in a mixture of carbon-tetrachloride (a solvent) and thionyl chloride, and excess thionyl chloride and carbon tetrachloride (solvent) are distilled off under reduced pressure to obtain a 4-alkoxycarbonyloxy benzoic acid chloride (Formula 7). Then, in the presence of a base such as trimethylamine, the 4-hydroxyphenyl acrylate (Formula 6) and the 4-alkoxycarbonyloxy benzoic acid chloride (Formula 7) are reacted to obtain the compound 5.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[N:26]=3)=[CH:21][CH:20]=2)[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[C:38]1([OH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O1CCOCC1>CN(C=O)C>[F:31][C:27]1[N:26]=[C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][N:3]3[C:2]([O:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[C:10]4[C:5]([N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7](=[O:13])[N:8]([CH3:12])[C:9]4=[O:11])=[N:4]3)=[CH:20][CH:21]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Oc1ccccc1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Oc3ccccc3)n(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Temperature: 150 °C
Yield: 67.4 %

Procedure:
3-chloro-2-(4-(6-fluoropyridin-2-yl)benzyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (40 mg, 0.095 mmol), potassium carbonate (40 mg, 0.28 mmol) and phenol (26 mg, 0.28 mmol) are placed in a Biotage microwave vial, and then 0.4 mL of dioxane is added. The vial is sealed, and then heated in a Biotage microwave instrument at 150° C. for 3 h. The reaction mixture is diluted with DMF, and then filtered. The filtrate is purified with a semi-preparative HPLC to give 32 mg of pure product as pale yellow crystals (Purity: 99.9%). MS (ESI) m/z 500.2 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:4][C@H:3]1[OH:13].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.O>O1CCOCC1>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C@H:2]2[C@H:3]([OH:13])[CH2:4][N:5]([CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:6]2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N[C@@H]1CN(C2CCCCC2)C[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@@H]1CN(C2CCCCC2)C[C@H]1O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 36.8 g of trans-4-amino-1-cyclohexyl-3-pyrrolidinol in 600 ml of p-dioxane was mixed with 40 g of powdered anhydrous potassium carbonate and stirred while 35.0 g of p-chlorobenzoyl chloride in 100 ml of p-dioxane was added dropwise. The mixture was stirred at room temperature for 2 hrs, then heated at reflux for 2 hrs. While still hot, 10 ml of water was added to make the precipitate granular; the mixture was filtered and the dioxane reduced to one-half volume. This solution was poured into one liter of water. The precipitate was collected and recrystallized from acetone. Yield was 60.5 g (94%), m.p. 193°-195° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:32]([N:33]2[CH2:38][CH2:37][CH:36]([C:39]([F:42])([F:41])[F:40])[CH2:35][CH2:34]2)=[CH:31][C:9]2[N:10]([CH3:30])[C:11]([NH:13][C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:15]=3[Cl:29])=[N:12][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[Cl:29][C:15]1[C:16]([CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[NH:13][C:11]1[N:10]([CH3:30])[C:9]2[CH:31]=[C:32]([N:33]3[CH2:34][CH2:35][CH:36]([C:39]([F:42])([F:41])[F:40])[CH2:37][CH2:38]3)[C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=2[N:12]=1
Reactant: CCOC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)n(C)c2cc1N1CCC(C(F)(F)F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)cc21
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-[4-trifluoromethyl-piperidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid ethyl ester (550 mg, 0.86 mmol), 1 N NaOH-solution (10 ml) and dioxane (20 ml) is stirred for 24 h at 100° C. and acidified with 1 N HCl (to pH ˜5). The mixture is extracted with EtOAc and the organic layer is washed with brine, dried with Na2SO4, filtered and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:19][C:18]2[C:13](=[N:14][C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:16][CH:17]=2)[N:12]([C@:29](O[SiH3])([CH3:47])[C:30](C2C=CC=CC=2)(C2C=CC=CC=2)C(C)(C)C)[C:11]1=[O:50].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:69]1CCCC1>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:19][C:18]2[C:13](=[N:14][C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:16][CH:17]=2)[N:12]([C@@H:29]([CH3:47])[CH2:30][OH:69])[C:11]1=[O:50]
Reactant: C1CCOC1
Reactant: COc1ccc(Nc2ncc3c(n2)N([C@@](C)(O[SiH3])C(c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)N(c2ccc(OC)cc2F)C3)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1ccc(Nc2ncc3c(n2)N([C@@H](C)CO)C(=O)N(c2ccc(OC)cc2F)C3)cc1
Reaction time: 4 h

Procedure:
(S)-3-(2-Fluoro-4-methoxy-phenyl)-1-(2-tert-butyl-diphenyl-silanyloxy-1-methyl-ethyl)-7-(4-methoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.25 g, 0.35 mmol) was dissolved in anhydrous tetrahydrofuran (2.5 mL) and treated with tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 1.40 mL, 1.400 mmol). The reaction was stirred in a water bath that was maintained in the 30–40° C. range. The reaction was complete after 4 hours and was concentrated. This residue was redissolved in ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, concentrated and then purified by flash chromatography (Biotage 40S, 75:25 ethyl acetate-hexanes) to give (S)-(+)-3-(2-fluoro-4-methoxy-phenyl)-1-(2-hydroxy-1-methyl-ethyl)-7-(4-methoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a pale yellow foam. (Yield 0.14 g, 85.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1>>[C:15]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:14]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1cccc(-c2ccccc2)c1)c1cc(Cl)ccc1O
Yield: 75.6 %

Procedure:
Using 5-chlorosalicylic acid and 3-aminobiphenyl as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-].C(C1C=CC=C(C(C)(C)C)C=1O)(C)(C)C.[CH3:47][S:48][CH2:49][CH2:50]O.[CH:52]1([CH2:55][C:56]2[C:61]3[S:62][C:63]([CH2:66][C:67]4[CH:72]=[CH:71][CH:70]=[C:69]([C:73]([F:76])([F:75])[F:74])[CH:68]=4)=[C:64]([OH:65])[C:60]=3[C:59](=[O:77])[N:58]([CH3:78])[N:57]=2)[CH2:54][CH2:53]1>O1CCCC1>[CH:52]1([CH2:55][C:56]2[C:61]3[S:62][C:63]([CH2:66][C:67]4[CH:72]=[CH:71][CH:70]=[C:69]([C:73]([F:76])([F:75])[F:74])[CH:68]=4)=[C:64]([O:65][CH2:50][CH2:49][S:48][CH3:47])[C:60]=3[C:59](=[O:77])[N:58]([CH3:78])[N:57]=2)[CH2:53][CH2:54]1
Reactant: Cn1nc(CC2CC2)c2sc(Cc3cccc(C(F)(F)F)c3)c(O)c2c1=O
Reactant: CSCCO
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCOc1c(Cc2cccc(C(F)(F)F)c2)sc2c(CC3CC3)nn(C)c(=O)c12
Reaction time: 18 h

Procedure:
To 5 ml of dry tetrahydrofuran was added 0.64 ml of 1M triphenylphosphine in tetrahydrofuran followed by 0.64 ml of 1M diethyl diazodicarboxylate in tetrahydrofuran and then by 0.64 ml of 1M 2,6-di-t-butylphenol in tetrahydrofuran. This mixture was mixed for 5 minutes and then 1.28 ml of 0.5M 2-(methylthio)ethanol in tetrahydrofuran was added. The solution was then mixed for 5 minutes. 7-Cyclopropylmethyl-3-hydroxy-5-methyl-2-[(3-trifluoromethylphenyl)methyl]thieno[2,3-d]pyridazin-4(5H)-one (248 mg in 1 ml tetrahydrofuran) was added and the solution was mixed periodically over 24 hours. The solution was opened to the air for 18 hours and then purified by chromatography, eluting with an isohexane ethyl acetate gradient, to give the title compound (77 mg).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[CH:17]=[O:18])[CH:20]=1
Reactant: OB(O)c1cccnc1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(I)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Temperature: 95 °C
Yield: 47 %

Procedure:
5-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXIV) (1.53 g, 4.30 mmol), pyridine-3-boronic acid (CXXXI) (0.58 g, 4.73 mmol), and potassium phosphate tribasic (1.37 g, 6.45 mmol) was dissolved in 1,4-dioxane (43.0 mL) and water (9.0 mL) Tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.4301 mmol) was added, and the reaction was heated to 95° C. for 2.5 h. The solvent was removed, and the residue was partitioned between EtOAc and water. The organic phase was separated and washed sequentially with water and brine. The material was dried (MgSO4), concentrated, and purified by flash chromatography using a 40 g Thomson normal phase silica gel cartridge (100% hexanes→1:1 EtOAc:hexanes) to afford 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXXXII) (0.62 g, 2.02 mmol, 47% yield) as a tan amorphous solid. 1H NMR (DMSO-d6) δ ppm 10.23 (s, 1H), 8.95 (d, J=2.3 Hz, 1H), 8.61 (dd, J=4.8, 1.5 Hz, 1H), 8.39 (d, J=0.98 Hz, 1H), 8.17-8.14 (m, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.95-7.93 (m, 1H), 7.64-7.60 (m, 1H), 6.13 (dd, J=9.4, 2.4 Hz, 1H), 3.93-3.90 (m, 1H), 3.86-3.81 (m, 1H), 2.45-2.41 (m, 1H), 2.11-2.07 (m, 2H), 1.82-1.78 (m, 1H), 1.66-1.62 (m, 2H); ESIMS found for C18H17N3O2 m/z 308 (M+H).
Reaction SMILES: CC([C@H](NC(OCC1C=CC=CC=1)=O)C(O)=O)C.C([O:26][C:27]([C:29]1([OH:63])[CH2:34][CH:33]([OH:35])[CH:32]([NH:36][C:37](=[O:39])[CH3:38])[CH:31]([CH:40]([OH:62])[CH:41]([OH:61])[CH2:42][O:43][C:44](=[O:60])[CH:45]([NH:49]C(OCC2C=CC=CC=2)=O)[CH:46]([CH3:48])[CH3:47])[O:30]1)=[O:28])C1C=CC=CC=1>C1COCC1.C(OCC)(=O)C.[Pd]>[C:37]([NH:36][CH:32]1[CH:31]([CH:40]([OH:62])[CH:41]([OH:61])[CH2:42][O:43][C:44](=[O:60])[CH:45]([NH2:49])[CH:46]([CH3:48])[CH3:47])[O:30][C:29]([OH:63])([C:27]([OH:28])=[O:26])[CH2:34][CH:33]1[OH:35])(=[O:39])[CH3:38]
Reactant: CC(=O)NC1C(O)CC(O)(C(=O)OCc2ccccc2)OC1C(O)C(O)COC(=O)C(NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Agent: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NC1C(O)CC(O)(C(=O)O)OC1C(O)C(O)COC(=O)C(N)C(C)C
Reaction time: 8 h
Yield: 80 %

Procedure:
In a 500 mL Parr shaker is placed the Z-valine protected benzyl ester (1-5) (2.50 g, 3.96 mmol) and the solid is dissolved in a mixture of THF (22 mL) and ethyl acetate (10 mL). To this is then added 10% Palladium on Carbon (2.0 g) in a single lot and the resulting suspension is hydrogenated at 50 psi at room temperature for overnight. LC/MS at this time of a small filtered aliquot, shows complete absence of starting material and the presence of the desired material (M+1=409). The remaining suspension is filtered through a Celite pad and the pad washed with THF. Evaporation of solvent leaves a light yellow semi-solid which upon trituration with isopropanol produces an off-white solid. The solid is collected by filtration through a Buchner funnel to provide 1.28 g (80% yield) of essentially pure pro-drug ester 1. LC/MS: (+) ESI: m/z=409.0 [M+1]; retention time=0.40 min. Melting Point: Decomposes between 140 to 145° C. Appearance: Off-white solid. Analytical HPLC; Column=Phenomenex Luna HILIC (reverse phase): Mobile Phase: A=0.05% H3PO4 in Water, B=0.05% H3PO4 in CH3CN: Gradient: 5% A to 50% B over 20 minutes, λ=205 nM; Retention Time: 3.8 minutes (Single Peak). 1H NMR (400 MHz, d4-MeOD) δ 4.41-4.49 (m, 2H), 3.98-4.08 (m, 3H), 3.87-3.97 (m, 2H), 3.57 (dd, J=9.6, 0.8 Hz, 1H), 2.28-2.39 (m, 1H), 2.22 (dd, J=12.8, 4.8 Hz, 1H), 2.04 (s, 3H), 1.83 (dd, J=12.8, 11.6 Hz, 1H), 1.04-1.06 (m, 6H); 13C NMR (400 mHz, D2O) δ 176.6, 174.6, 169.9, 96.4, 69.9, 68.4, 67.8, 67.4, 67.2, 58.4, 52.3, 39.4, 29.4, 22.1, 17.3, 17.1. Final Purity Estimate: 96-97% (Based upon 1H NMR integration in Trifluoroacetic Acid-D).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Br:22])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc(OCc2ccccc2)cc1C(F)(F)F
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1cc(OCc2ccccc2)ccc1CBr
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of [4-[(phenylmethyl)oxy]-2-(trifluoromethyl)phenyl]methanol (for a preparation see Intermediate 18)(3.11 g, 11.02 mmol) in DCM (40 ml) under nitrogen in an ice-water bath was added a solution of phosphorus tribromide (1.09 ml, 11.6 mmol, Aldrich) in DCM (20 ml). The solution was allowed to warm to ambient temperature and stirred for 1.5 h. The reaction mixture was poured onto ice-water (150 ml) and saturated aqueous sodium hydrogen carbonate (75 ml). The mixture was diluted with dichloromethane (100 ml), and the phases separated. The aqueous extract was washed with dichloromethane (50 ml). The combined organic extracts were washed with water (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to give 4-(bromomethyl)-3-(trifluoromethyl)phenyl phenylmethyl ether as a white solid (2.96 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]1[N:12]2[C:13](=[O:19])[NH:14][C:15]3=[CH:16][CH:17]=[CH:18][C:10](=[C:11]23)[O:9][CH2:8]1.C(O)(=O)C.[Br:24]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:24][C:18]1[C:10]2[O:9][CH2:8][CH:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]3)[N:12]3[C:13](=[O:19])[NH:14][C:15]([C:11]=23)=[CH:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]c2cccc3c2n1C(C1CCCCN1)CO3
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2ccc(Br)c3c2n1C(C1CCCCN1)CO3
Reaction time: 2 h
Yield: 84.5 %

Procedure:
The 4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (0.20 g, 0.77 mmol) of Step 1 was dissolved in acetic acid (10.0 mL, 176 mmol) at room temperature and N-bromosuccinimide (0.14 g, 0.77 mmol) was slowly added. The reaction was stirred for 2 h and was concentrated in vacuo to give a residue. The residue was dissolved in ethyl acetate, washed with aqueous potassium carbonate, washed with brine, dried over magnesium sulfate, and concentrated to give 7-bromo-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as a dark oil (0.22 g, 85%). LCMS calculated for C14H17BrN3O2 (M+H)+: m/z=338.0, 340.0. found: 338.0, 340.0.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[N:46]([CH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)=[C:47]=[O:48]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([C@@H:40]1[CH2:44][CH2:43][N:42]([C:47]([NH:46][CH:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)=[O:48])[CH2:41]1)=[O:39]
Reactant: O=C=NC1CCCC1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)[C@@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)[C@@H]1CCN(C(=O)NC2CCCC2)C1
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using (3R)—N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate) and isocyanatocyclopentane as starting materials in 43% yield. LCMS for C29H33ClN7O2 (M+H)+: m/z=546.2.
Reaction SMILES: [C:1]([NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[OH:35])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1C1C=CC(O)=C(C(O)=O)C=1>>[C:1]([NH:24][CH2:25][CH2:26][NH:27][C:28]([C:29]1[CH:34]=[C:33]([C:41]2[CH:40]=[CH:39][C:38]([F:37])=[CH:43][C:42]=2[F:44])[CH:32]=[CH:31][C:30]=1[OH:35])=[O:36])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)c1ccccc1O
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)c1cc(-c2ccc(F)cc2F)ccc1O

Procedure:
N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2′,4′-difluoro-4-hydroxybiphenyl-3-carboxamide was prepared in a similar fashion as N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxybenzamide, using the appropriate 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid starting material. Mass calculated for C37H44F2N2O3=602.75. found: [M+H]+=603.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.C(O)(C(F)(F)F)=O>ClCCl>[F:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=1[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)ccc4F)cc3)c3c(N)ncnc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3cc(F)ccc3F)cc1)nn2[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 110.1 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl (3R)-3-[4-amino-3-[4-(2,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (450 mg, 0.86 mmol, 1.00 equiv) in dichloromethane (40 mL). This was followed by the addition of CF3COOH (10 mL) dropwise with stirring at 25° C. over 5 min. The resulting solution was stirred for 3 h at 25° C. and then concentrated under vacuum. The residue was diluted with dichloromethane and the resulting mixture was washed with aqueous sodium bicarbonate and brine and dried over anhydrous sodium sulfate and concentrated under vacuum to give 400 mg (99%) of 3-[4-(2,5-difluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Br:11])[CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[Br:11][C:4]1[CH:3]=[C:2]([I:1])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:17][CH3:18])=[O:7]
Reactant: CCO
Reactant: O=C(O)c1ccc(I)cc1Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(I)cc1Br
Temperature: 80 °C
Yield: 92 %

Procedure:
To a stirred solution of 4-iodo-2-bromobenzoic acid (5 g, 15.29 mmol) in ethyl alcohol (EtOH; 100 mL) was added sulfuric acid (H2SO4; 5 mL), and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with EtOAc (2×100 mL) and washed with H2O (100 mL). The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the compound as a pale yellow solid (5 g, 92%): 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J=1.2 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:27][CH:28]2[CH2:30][CH2:29]2)=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nn1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCC2CC2)nn1
Temperature: 25 °C
Reaction time: 60 h
Yield: 94 %

Procedure:
A solution of n-butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxylate (reference example 3) (0.286 g, 0.69 mmol) in DMF (3.5 ml) was treated with bromomethylcyclopropane (0.1 g, 0.78 mmol) and potassium carbonate (0.473 g, 3.4 mmol). The reaction was allowed to stir at ambient temperature for 60 hours. The solvent was evaporated at reduced pressure (vacuum pump) and the residue partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×10 ml). The organic layers were combined dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant ethyl acetate/hexane) to give the title compound as a pale yellow oil (0.3 g, 94%).