Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(Cl)[Cl:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][Si:17]([CH3:20])([CH3:19])[OH:18].C(N(CC)CC)C>O1CCCC1>[CH3:16][Si:17]([CH3:20])([CH3:19])[O:18][Si:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[Cl:8]
Reactant: C[Si](C)(C)O
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)O[Si](Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
The following were ingredients were introduced into a stirrer-equipped four-neck flask: 164.8 g (651.2 mmol) diphenyldichlorosilane and 300 mL tetrahydrofuran. The resultant mixture was stirred at room temperature while a mixture of 60 g (542.7 mmol) of 81.4% pure trimethylsilanol and 65.9 g (651.2 mmol) of triethylamine was added dropwise. Stirring at room temperature was continued for an additional hour following completion of the addition, at which time the salt formed as a by-product of the reaction was removed by filtration. The filtrate was then distilled under reduced pressure to yield 118.7 g of a fraction boiling at 136.5° C.-142° C. under of 2 mm Hg, equivalent to a 71.4% yield of trimethylsiloxydiphenylchlorosilane. Analysis of this product by gas chromatography (GLC), nuclear magnetic resonance (NMR), and infrared spectrochemical analysis (IR) confirmed it to be trimethylsiloxydiphenylchlorosilane with the following structural formula. ##STR6##
Reaction SMILES: [F:1][C:2]([F:19])([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1)[CH:3]([F:9])[O:4][C:5]([F:8])([F:7])[F:6].[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27]([SH:32])[CH:26]=[N:25]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27]([S:32][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][C:2]([F:19])([F:1])[CH:3]([F:9])[O:4][C:5]([F:8])([F:7])[F:6])=[CH:12][CH:13]=2)[CH:26]=[N:25]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: FC(OC(F)(F)F)C(F)(F)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)n1ncc(SCc2ccc(OC(F)(F)C(F)OC(F)(F)F)cc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
1.4 g of 4-(1,1,2-trifluoro-2-trifluoromethoxy-ethoxy)-benzyl bromide (Example 4) and 1 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone are added to a suspension of 0.8 g of potassium carbonate in 10 cc of dimethylformamide. The resulting reaction mixture is stirred for 1 hour at room temperature, is diluted with ether, is washed with diluted HCl and brine; the washed solution is thoroughly dehydrated, the solvent is evaporated off and the so obtained raw reaction product is chromatographed on silica gel with 9/1 hexane/ethyl acetate. 1.4 g of pure product is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[O:22][N:21]=2)=[O:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH:15]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=3)[O:22][N:21]=2)=[O:19])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cc(-c3ccc(C#N)cc3)on2)C2CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(-c2cc(C(=O)N(C3CCNCC3)C3CC3)no2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-{[5-(4-cyano-phenyl)-isoxazole-3-carbonyl]-cyclopropyl-amino}-piperidine-1-carboxylic acid tert-butyl ester (90 mg) and trifluoroacetic acid (0.20 mL) in dichloromethane (3 mL) is stirred for 3 h at room temperature. The reaction mixture is diluted with dichloromethane prior to the addition of 2 N aqueous NaOH solution (1.5 mL) and aqueous Na2CO3 solution. The resulting mixture is stirred vigorously for 10 min. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined extracts are dried over MgSO4 and concentrated in vacuo to give the desired product. LC (method 4): tR=1.02 min; Mass spectrum (ESI+): m/z=337 [M+H]+.
Reaction SMILES: [C:1]([CH:5]1[CH2:26][CH2:25][C:8]2([O:12][CH:11]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([CH:5]1[CH2:26][CH2:25][C:8]2([O:12][CH:11]([CH2:13][NH2:14])[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC2(CC1)OCC(CN1C(=O)c3ccccc3C1=O)O2
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)C1CCC2(CC1)OCC(CN)O2
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a warm (50° C.) solution of 8-t-butyl-2-(phthalimidomethyl)-1,4-dioxaspiro(4,5)decane (12.5 g, 35 mmol) in ethanol (100 ml) was added hydrazine hydrate (3.6 g, 72 mmol). The reaction mixture was kept at 50° C. for 1 hour. Light petroleum 200 ml was added and insoluble material was filtered off. The solvent was evaporated in vacuo. The residue was dissolved in toluene (100 ml) washed with brine (100 ml) and dried (MgSO4). Evaporation of the solvent yielded the title compound as a yellow oil (7.2 g). GC analysis indicated the compound as existing as a mixture of two diastereoisomers (cis, cis and cis, trans) in a ratio of 48:52. The NMR spectra are in agreement with the assigned structure.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@H:12]2[O:21][C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([O:22][C:23](=[O:25])[CH3:24])[C@@H:14]([O:26][C:27](=[O:29])[CH3:28])[C@@H:13]2[O:30][C:31](=[O:33])[CH3:32])(=O)=O)=CC=1.CC(C)=O.[I-:39].[Na+]>O>[I:39][CH2:11][C@H:12]1[O:21][C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([O:22][C:23](=[O:25])[CH3:24])[C@@H:14]([O:26][C:27](=[O:29])[CH3:28])[C@@H:13]1[O:30][C:31](=[O:33])[CH3:32]
Reactant: CC(=O)O[C@@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)O[C@@H]1O[C@H](CI)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
6-O-(p-Toluenesulfonyl)-1,2,3,4-tetra-O-acetyl-β-D-glucose (5, 18.5 g, 36.8 mmol) was place in a 500-mL round-bottomed flask. Acetone (200 ml) and sodium iodide (18.5 g, 123 mmol) were added. The resulting mixture was heated at reflux for 20 h. The reaction proceeded gradually. The mixture was poured into 1000 ml of water, and the resulting solid was filtered with a glass filter. Recrystalization from ethanol afforded 6-deoxy-6-iodo-1,2,3,4-tetra-O-acetyl-β-D-glucose (compound 6) in 65% yield (11.0 g, 24.0 mmol).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.C1([Si](C2C=CC=CC=2)(C2C=CC=CC=2)Cl)C=CC=CC=1>N1C=CC=CC=1>[N:10]1[CH:2]=[C:3]2[C:7]([NH:6][CH:5]=[N:4]2)=[N:8][CH:9]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Agent: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: c1ncc2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.3 g of 6-chloro-9-β-D-ribofuranosyl-9H-purine and 15 g of triphenylchlorosilane were dissolved in 500 ml of pyridine and stirred for one hour at room temperature. Pyridine was distilled away and the residue was dissolved in benzene. The benzene layer was washed with 1N HCl and brine, and then dried over sodium sulfate anhydride. The solvent was distilled off and the residue was recrystallized from a mixture of hexane and ethyl acetate to give 21.5 g of 6-chloro-9-15-O-triphenylsilyl-β-D-ribofuranosyl)-9H-purine.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[C:18]([CH3:20])[N:19]=2)=[C:11]([O:27][CH3:28])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[C:18]([CH3:20])[N:19]=2)=[C:11]([O:27][CH3:28])[CH:10]=1
Reactant: [H][H]
Reactant: COc1cc(OCc2ccccc2)ccc1-c1nc(C)c(-c2cccnc2)[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(O)ccc1-c1nc(C)c(-c2cccnc2)[nH]1
Reaction time: 5 h
Yield: 28 %

Procedure:
To a solution of 2-(4-benzyloxy-2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (1.18 g) in methanol (12 ml) and tetrahydrofuran (6 ml) was added 10% palladium on carbon (wet ca. 50%, 0.30 g), and the mixture was stirred for 7 hours at ambient temperature under atmospheric pressure of hydrogen gas. The mixture was filtered, and the filtrate was evaporated. The residue was dissolved in methanol (20 ml), and hydrogenated again on palladium on carbon (wet, 0.50 g) for 5 hours. After the filtration, the filtrate was evaporated, and the residue was triturated in a mixture of diisopropyl ether and isopropanol (1:1 V/V) to give 2-(4-hydroxy-2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.25 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][CH:61]1[CH2:66][CH2:65][CH:64]([NH2:67])[CH2:63][CH2:62]1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:67][CH:64]3[CH2:65][CH2:66][CH:61]([CH3:60])[CH2:62][CH2:63]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: CC1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCC(NC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.2 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 4-methylcyclohexanamine (54.2 mg, 0.478 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to give the yellow title compound (192 mg). LC-MS (ES) m/z=451 [M+H]+.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=O)[CH2:2]1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:24]>C(Cl)Cl.CN(C=O)C>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([NH2:24])=[O:16])[CH2:2]1
Reactant: [NH4+]
Reactant: O=C(O)C1CCc2[nH]c3ccccc3c2C1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C1CCc2[nH]c3ccccc3c2C1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (30.4 g, 141 mmol), was suspended in 450 ml of methylene chloride and cooled to 0° C. Oxalyl chloride (14.8 mL, 169 mmol) was added dropwise, followed by two drops of DMF. The resulting mixture was allowed to warm to room temperature and was stirred for 24 h. After re-cooling to 0° C., 450 mL of conc. aqueous ammonium hydroxide were added dropwise. The yellow precipitate that formed was collected by vacuum filtration. After drying, the title compound weighed 17.4 g (58%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2Br)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([Sn](CCCC)(CCCC)/[CH:30]=[CH:31]\[CH2:32][OH:33])CCC>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:30]=[CH:31][CH2:32][OH:33])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCCC[Sn](/C=C\CO)(CCCC)CCCC
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2Br)ccc(Br)c1OC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2C=CCO)ccc(Br)c1OC
Temperature: 30 °C

Procedure:
Bis-(tri-tert-butylphosphine)palladium (0.031 g) was added to a degassed solution of methyl 3-bromo-6-(2-bromobenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 66, 0.286 g) and 3-tributylstannyl-(Z)-prop-2-en-1-ol (prepared according to Webb et al, Tetrahedron, 2008, 64, 4778, 0.27 ml) in toluene (3 ml) and the resultant mixture was stirred at room temperature for 3 hours then heated at 30° C. for 2 hours. After cooling, the mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60% to give methyl 3-bromo-6-((2-(3-hydroxyprop-1-enyl)benzenesulfonyl)methyl)-2-methoxybenzoate as a mixture of E and Z isomers.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([S:9](=[O:12])(=[O:11])[NH2:10])[C:6]([Cl:13])=[CH:5][C:3]=1[NH2:4].C(O)(=O)C.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[Cl:13][C:6]1[C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:2]2[NH:1][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:4][C:3]=2[CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Solvent: CC(=O)O
Solvent: CCO
Product: NS(=O)(=O)c1cc2[nH]c(-c3ccccc3)nc2cc1Cl

Procedure:
A mixture of 2.21 g. of 2-amino-4-chloro-5-sulfamylaniline (VI), 50 ml. of glacial acetic acid, and 1.05 g. of benzaldehyde was refluxed for 16 hours and then decanted into water. The precipitate was collected by filtration, dissolved in ethanol, treated with Darco, filtered through filter paper and then through Celite. Concentration in vacuo provided a solid which was dissolved in ethanol, filtered, and forced out with water. Treatment of this beige solid with boiling acetronitrile provided an off-white solid mp 314°-316°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[F:12][C:5]1[CH:4]=[C:3]([F:13])[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)c(F)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(NS(C)(=O)=O)c(F)cc1F
Reaction time: 24 h

Procedure:
To a solution of methyl 5-amino-2,4-difluorobenzoate (252 mg, 1.35 mmol) and pyridine (0.13 mL, 1.61 mmol) in 5 mL CH2Cl2 was added methanesulfonyl chloride (0.12 mL, 1.48 mmol). After 24 h at room temperature, the reaction mixture was washed with saturated aqueous NaHCO3 and extracted with CHCl3 to provide crude methyl 2,4-difluoro-5-[(methylsulfonyl)amino]benzoate as a solid (ESI-MS 264 (M−H)), which was hydrolyzed using aqueous NaOH to provide 2,4-difluoro-5-[(methylsulfonyl)amino]benzoic acid (ESI-MS 250 (M−H)), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30](OCC)=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:36]([CH2:38][NH2:39])[OH:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30]([NH:39][CH2:38][CH2:36][OH:37])=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O
Reactant: NCCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-piperidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.64-1.79 (m, 6 H), 2.19 (t, J=6.42 Hz, 2 H), 3.21 (t, J=5.58 Hz, 2 H), 3.33-3.48 (m, 4 H), 3.50-3.61 (m, 2 H), 4.15-4.25 (m, 4 H), 4.93 (t, J=5.05 Hz, 1 H), 7.10-7.18 (m, 2 H), 7.37-7.44 (m, 2 H), 8.00 (d, J=1.26 Hz, 1 H), 8.55 (d, J=1.26 Hz, 1 H), 10.41 (t, J=5.90 Hz, 1 H); ES+ MS: 497 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.Cl.[N+:12]([C:15]1[CH:16]=[C:17]([C:21]2[N:22]=[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[NH:24][CH:25]=2)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(O)(C)C.C(N(C(C)C)CC)(C)C>>[N+:12]([C:15]1[CH:16]=[C:17]([C:21]2[N:22]=[C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:2]4[N:7]=[CH:6][N:5]=[C:4]5[NH:8][N:9]=[CH:10][C:3]=45)[CH2:28][CH2:27]3)[NH:24][CH:25]=2)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: Clc1ncnc2[nH]ncc12
Reactant: O=[N+]([O-])c1cccc(-c2c[nH]c(C3CCNCC3)n2)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc(-c2c[nH]c(C3CCN(c4ncnc5[nH]ncc45)CC3)n2)c1
Temperature: 70 °C

Procedure:
Place 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (150 mg; 1.16 equiv; 970.50 μmoles; 150.00 mg), and 4-[4-(3-Nitro-phenyl)-1H-imidazol-2-yl]-piperidine hydrochloride salt (258 mg 1.00 equiv; 835.58 μmoles; 258.00 mg) in a microwave vial and dissolve in isopropyl alcohol (3 mL; 39.24 mmoles; 3.00 mL) and add diisopropylethylamine (0.5 mL; 2.87 mmoles; 500.00 μL). Heat the mixture to 70° C. in a Emrys Optimizer microwave for 1 hour while stirring. Filter, and concentrate filtrate to an oil. Combine solid and oil and dissolve in 3% MeOH/DCM. Purify using ISCO chromatography over a biotage 40S column eluting with a gradient of 2.5% MeOH/DCM to 10% MeOH/DCM at a flow rate of 40 mL/min. Collect appropriate fractions, concentrate to an oil. Dissolve oil in 10% MeOH/DCM and wash with a mixture of aqueous sodium bicarbonate/saturated aqueous sodium chloride three times. Wash the combined organic layers with saturated aqueous sodium chloride and dry over sodium sulfate. Concentrate and dry under reduced pressure to obtain the title compound.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:14]([C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1csc(Br)n1
Reactant: CNc1ccccc1
Product: CCOC(=O)Cc1csc(N(C)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A mixture of ethyl 2-bromo-4-thiazolylacetate (2.5 g) and N-methylaniline (2.1 g) is stirred at 150°-155° C for 30 minutes. The resultant solution is treated in the same manner as in Example 1 to give ethyl 2-(N-methylanilino)-4-thiazolylacetate (2.5 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CC(C)=O>[CH2:26]([O:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([O:8][CH2:14][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[CH:7]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1-c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1-c1ccccc1
Yield: 168.1 %

Procedure:
Compound 1 (1.81 g, 7.00 mmol) obtained in Example 1 was dissolved in acetone (50 mL), and potassium carbonate (5.88 g, 42.6 mmol) and benzyl bromide (3.33 mL, 28.0 mmol) were added thereto and stirred with heating under reflux for 1.5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane/ethyl acetate=20/1 to 9/1) to obtain methyl 3,5-bis(benzyloxy)-2-phenylphenylacetate (2.58 g, 84%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17](O)=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:17]([N:49]1[CH2:50][CH2:51][CH2:52][C@@H:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48]1)(=[O:18])[CH3:16]
Reactant: O=C(C[C@@H]1CCCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC[C@@H](CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 77 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[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]-2-[(3S)-piperidin-3-yl]acetamide tris(trifluoroacetate) and acetyl chloride as the starting materials in 77% yield. LCMS for C26H29ClN7O2 (M+H)+: m/z=506.0.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C1(C)C=CC=CC=1.[CH2:26]1[O:34][C:33]2[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=2[O:27]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:1]([C:3]1[CH:17]=[C:16]([C:31]2[CH:30]=[CH:29][C:28]3[O:27][CH2:26][O:34][C:33]=3[CH:32]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1cc(-c2ccc3c(c2)OCO3)c2c(c1)ncn2-c1ccccc1

Procedure:
5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 3,4-methylene dioxyphenylboronic acid (83 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) were combined and the mixture was stirred at reflux overnight The solvent was removed under reduced pressure and the crude product was purified on a 2 g silica Isolute® SPE column, eluting with dichloromethane/methanol (95:5). The eluent was concentrated under reduced pressure and product was crystallised from dichloromethane/diethyl ether to the title compound (75 mg, 44%) m/z, 339.8 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:4]([OH:6])=O.Cl.[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[OH:1][CH2:2][C@@H:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:4]([NH:22][O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: C=CCCCC[C@H](CO)C(=O)O
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CCCCC[C@H](CO)C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2R)-2-(hydroxymethyl)-7-octenoic acid (1.12 g, 6.51 mmol), O-benzyl hydroxylamine hydrochloride (1.04 g, 6.51 mmol) and 4-dimethylamino-pyridine (1.90 g, 15.62 mmol) in dichloromethane (30 mL) at 0° C. was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.50 g, 7.81 mmol). After stirring at room temperature overnight, the reaction was then quenched with 1N aqueous HCl solution (25 mL) and extracted using dichloromethane (25 mL×2). The organic extracts were washed with water, brine, and dried over MgSO4. Removal of the solvent under reduced pressure yielded the title compound. MH+278.