Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:18])=[N:4][N:3]=1.[C:19]([O:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][N:25]=1)([CH3:22])([CH3:21])[CH3:20].P(=O)(O)(O)O.[K]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].F[B-](F)(F)F.C1([PH+](C2CCCCC2)C2CCCCC2)CCCCC1>[C:19]([O:23][C:24]1[CH:29]=[C:28]([C:2]2[C:11]3[C:6](=[C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:8]=[CH:9][CH:10]=3)[C:5]([Cl:18])=[N:4][N:3]=2)[CH:27]=[CH:26][N:25]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Clc1nnc(Cl)c2c(-c3ccccc3)cccc12
Reactant: CC(C)(C)Oc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: [Pd]
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)Oc1cc(-c2nnc(Cl)c3c(-c4ccccc4)cccc23)ccn1
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
To a solution of 1,4-dichloro-5-phenylphthalazine (0.400 g, 1.45 mmol), 2-(tert-butoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.484 g, 1.75 mmol) in dioxane (20 mL) and water (2 mL) was added phosphoric acid, potassium salt (0.617 g, 2.91 mmol). The reaction mixture was purged with nitrogen gas for 30 min and then Pd2(dba)3 (0.013 g, 0.015 mmol) was added followed by tricyclohexylphosphonium tetrafluoroborate (11 mg, 0.029 mmol). The purging was continued for a further 15 min and the reaction mixture heated to 95° C. for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography using Combiflash Isco (REDISEP®, SiO2, 12 g, 0-30% ethyl acetate/petroleum ether) to get 1-(2-(tert-butoxy)pyridin-4-yl)-4-chloro-5-phenylphthalazine (0.400 g, 33.2%) as a brown solid. LCMS (Condition 11): retention time 1.22 min, [M+1]=390.2. 1H NMR (400 MHz, DMSO-d6) δ 1.70 (s, 9 H), 6.84 (br s, 1 H), 7.05 (dd, J=1.2 Hz, J=5.2 Hz, 1 H), 7.36-7.44 (m, 2 H), 7.47-7.51 (m, 3 H), 8.06 (dd, J=1.2 Hz, J=7.6 Hz, 1 H), 8.15 (dd, J=0.8 Hz, J=4.8 Hz, 1 H), 8.26 (dd, J=7.2 Hz, J=8.0 Hz, 1 H), 8.47 (d, J=1.2 Hz, J=8.4 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[Br:15][CH2:16][C:17](Br)=[O:18]>C1(C)C=CC=CC=1>[Br:15][CH2:16][C:17]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(Cl)cn1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(CBr)Nc1ccc(Cl)cn1

Procedure:
To a solution of 5 g 5-Chloro-pyridin-2-ylamine and 1.5 ml pyridine in 30 ml toluene, 8 g bromo-acetyl bromide dissolved in 10 ml toluene was added dropwise under ice cooling. After 2 h the precipitate was isolated by filtration and recristallized from toluene to yield a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:17]([C:18]#[CH:19])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].Br[C:21]1[S:22][CH:23]=[CH:24][N:25]=1>C(N(CC)CC)C.C(OCC)(=O)C.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.[Cu](I)I>[NH2:1][C:2]1[C:17]([C:18]#[C:19][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: Brc1nccs1
Reactant: C#Cc1cccc(C(=O)OCc2ccccc2)c1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1c(C#Cc2nccs2)cccc1C(=O)OCc1ccccc1
Yield: 82 %

Procedure:
A solution of benzyl 2-amino-3-ethynylbenzoate (3.06 g), 2-bromothiazole (1.65 mL), bis(triphenylphosphine)palladium(II) dichloride (0.704 g) and copper iodide (0.232 g) in triethylamine (60 mL) was stirred under a nitrogen atmosphere at 60° C. for 1.5 hr with heating. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50) to give the title compound (3.32 g, yield 82%) as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[N+:11]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][CH:18]2[OH:23])([O-:13])=[O:12]>C1(C)C=CC=CC=1>[C:1]([O:23][CH:18]1[C:19]2[C:15](=[C:14]([N+:11]([O-:13])=[O:12])[CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1cccc2c1CCC2O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC1CCc2c1cccc2[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 100.9 %

Procedure:
A stirred solution of 40.0 g (0.51 mole) of acetyl chloride and 43.9 g (0.56 mole) of pyridine in 100 mL of toluene was cooled to 5° C., and a solution of 83.0 g (0.46 mole) of 4-nitro-1-indanol in 30 mL of toluene was added dropwise. Upon complete addition, the reaction mixture was stirred at 5° C. for 10 minutes, then was allowed to warm to ambient temperature and was stirred for 16 hours. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure to give 102.7 g of 4-nitro-1-indanyl acetate as an oil.
Reaction SMILES: [CH2:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:13]([N:16]([CH2:20][CH:21]=[CH2:22])[C:17](Cl)=[O:18])[CH:14]=[CH2:15].O1CCCC1>C(N(CC)CC)C>[CH2:13]([N:16]([CH2:20][CH:21]=[CH2:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH:14]=[CH2:15]
Reactant: CCCCS(=O)(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)CCCC)n1

Procedure:
A mixture of 5.7 g. 3-butylsulphonyl-1,2,4-triazole, 5.3 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 1.5 hours. The reaction mixture was worked up as described in Example 1 to give 1-diallylcarbamoyl-3-butylsulphonyl-1,2,4-triazole as an oil which was heated under reduced pressure (100°C./0.5 mm.) for 30 minutes to remove all traces of volatile material. Refractive index of product nD26 1.5132. Elemental analysis satisfactory.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[Li]CCCC.CN([CH:19]=[O:20])C.Cl>C(OCC)C.CCCCCC.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:19]=[O:20])=[CH:3][C:4]=1[CH2:9][CH3:10]
Reactant: CN(C)C=O
Reactant: CCc1cc(Br)ccc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CCc1cc(C=O)ccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a solution of 4.319 g of 4-bromo-1-chloro-2-ethyl-benzene (20 mmol) in 50 ml diethylether, cooled to 0° C., were added dropwise 12.3 ml of 1.6M n-BuLi in hexane. After 30 min. stirring at 0° C. and 2 h at RT, a solution of 2.43 ml DMF (31 mmol) in 10 ml diethylether was added dropwise (temperature raised from 20 to 28° C.). After 1 h additional stirring at RT, the reaction mixture was acidified with 2N HCl, diluted with 150 ml water and extracted with diethylether. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by flash column chromatography (heptane/AcOEt: 95/5) to yield 2.1 g of a colorless oil. MS (ISP) 168.1 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]([O:9]C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:11][NH2:12].O>C(O)(C)C>[CH:1]1([C:7]([NH:11][NH2:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CCCCC1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: NNC(=O)C1CCCCC1

Procedure:
28 Grams of methyl cyclohexylcarboxylate and 15 g of 85%--NH2NH2.H2O were dissolved in 50 ml of isopropyl alcohol, and the solution was refluxed by heating for 10 hours. The reaction mixture was concentrated, and the crystals precipitated by adding water were collected by filtration, then the crystals were washed with water, then recrystallized from water to yield 20 g of cyclohexane-carbohydrazide in the form of colorless needle-like crystals. Melting point: 155.5°-156.5° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]([CH3:18])[S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[CH:2]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]([CH3:18])[S:14]([CH3:17])(=[O:15])=[O:16])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:1]
Reactant: COC(=O)c1cc(CO)cc(N(C)S(C)(=O)=O)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C=O)cc(N(C)S(C)(=O)=O)c1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
A mixture of methyl 3-(hydroxymethyl)-5-[methyl(methylsulfonyl)amino]benzoate obtained in Reference Example 21 1.10 g (4.0 mmol), manganese dioxide 3.38 g (39 mmol) and ethyl acetate (40 mL) was stirred at 70° C. for 2.5 hours. The mixture was filtered on Celite to remove the precipitates, and the solvent was concentrated to give 0.847 g (3.1 mmol) of the title compound (yield: 78%).
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C@H:11]1[NH:16][C:15](=[O:17])[C@@H:14]([C@@H:18]([CH3:21])[CH2:19][CH3:20])[N:13]([CH:22]([C:26]2[C:27]([CH3:33])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[C:23](O)=[O:24])[C:12]1=[O:34].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>ClCCl>[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C@H:11]1[NH:16][C:15](=[O:17])[C@@H:14]([C@@H:18]([CH3:21])[CH2:19][CH3:20])[N:13]([C@H:22]([C:26]2[C:27]([CH3:33])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[C:23]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:24])[C:12]1=[O:34]
Reactant: C1COCCN1
Reactant: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)O)c1ccc(C)nc1C
Agent: Cl
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N1CCOCC1)c1ccc(C)nc1C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
A suspension of {(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}(2,6-dimethyl-3-pyridinyl)acetic acid hydrochloride (5.0 g, 10.3 mmol) (intermediate 5) in dry dichloromethane (50 ml) was treated with 1,1-carbonyldiimidazole (2.6 g, 16 mmol) and the reaction mixture was stirred under nitrogen for 18 hours. Morpholine (4.8 ml, 55 mmol) was added and the resultant solution was left to stand under nitrogen for 18 hours. The solvent was removed in vacuo and the residue was separated between ethyl acetate and water. The organic phase was washed with brine and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was dissolved in dichloromethane. This was applied to a basic alumina cartridge (240 g) and eluted using a gradient of 0-7.5% methanol in diethyl ether (9CV), 7.5-10% methanol in diethyl ether (1CV) and 10% methanol in diethyl ether (1CV). The required fractions were combined and evaporated in vacuo to give (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione as a white solid (2.4 g, 45%).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:14][C:15]([Si](C)(C)C)([F:17])[F:16].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([OH:13])[C:15]([F:17])([F:16])[F:14])=[CH:10][N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(N2CCCC2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(N2CCCC2)nc1)C(F)(F)F
Yield: 93.9 %

Procedure:
According to Reference Example 8-12, by use of 6-(pyrrolidin-1-yl)-3-pyridinecarboxaldehyde (173 mg, 0.982 mmol), (trifluoromethyl)trimethylsilane (174 μL, 1.18 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 98.0 μL, 0.098 mmol) and tetrahydrofuran (5.0 mL), the mixture was stirred and reacted at room temperature for 30 minutes. Then, slurry purification was performed using hexane, to give 2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoro-1-hydroxyethyl)-pyridine (Compound DH) (227 mg, yield: 94%).
Reaction SMILES: [OH:1]O.[CH:3]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1>C(O)(C)(C)C>[O:1]1[CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:3]12
Reactant: C1=CCCCCCCCCCC1
Reactant: OO
Solvent: CC(C)(C)O
Product: C1CCCCCC2OC2CCCC1
Reaction time: 1 h
Yield: 99 %

Procedure:
20 mg of solid tetramethyltetraoxodirhenium (VI) (CH3)4Re2O4 were added to a 5 ml portion of the "oxidation solution" initially prepared according to B) from tertbutanol and H2O2. This immediately produced a yellow coloration. 0.15 ml of cyclododecene was then added. This caused slight heating of the solution. After 1 hour, the mixture was worked up as in Examples 1-34 and analyzed (GC/IR/MS). 99% pure epoxycyclododecane was obtained by this procedure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH:22]1([C:25](O)=[O:26])[CH2:24][CH2:23]1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:25]([CH:22]4[CH2:24][CH2:23]4)=[O:26])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)C1CC1
Product: Cc1ccc(NC(=O)C2CC2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)cyclopropanecarboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and cyclopropanecarboxylic acid using method D. NMR; δH [2H6]—DMSO 10.18,(1H, s), 8.60,(1H, t), 7.91,(2H, d), 7.50-7.47,(2H, m), 7.40,(2H, d), 7.21,(1H, d), 3.16,(2H, t), 2.16,(3H, s), 1.74,(1H, m),1.04,(1H, m), 0.77-0.75,(4H, m), 0.43,(2H, m), 0.23,(2H, m). LCMS: retention time 3.19 min, MH+349.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=2[CH2:32][CH2:33][CH3:34])[C:9]=1[CH2:35][CH2:36][CH3:37])C.[Na].Cl>CO.[OH-].[Na+]>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][C:4]([OH:38])=[O:3])=[C:9]([CH2:35][CH2:36][CH3:37])[C:10]=1[O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=1[CH2:32][CH2:33][CH3:34])(=[O:16])[CH3:15]
Reactant: CCCc1c(OCCCOc2c(C(C)=O)ccc(OCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCCc1c(OCCCOc2c(C(C)=O)ccc(OCCC(=O)O)c2CCC)ccc(C(C)=O)c1O

Procedure:
A mixture of 5.4 g of racemic-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]methylacetic acid ethyl ester in 100 ml of methanol and 50 ml of 1N sodium hydroxide was stirred at reflux for 2 hours. The methanol was removed in vacuo and the pH of the residue was adjusted to 2.0 with 6N hydrochloric acid. The gummy product was extracted with methylene chloride and the extract was dried over magnesium sulfate and concentrated in vacuo to an oil. The crude acid was dissolved in 50 ml of methanol and 10 ml of 1.0N sodium hydroxide was added. The methanol was removed in vacuo, 25 ml of water was added and the sodium salt (0.33 molar hydrate) of racemic-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]methylacetic acid was filtered and dried to give 4.2 g (78%), mp 92°-95°. The sodium salt was converted with 1N hydrochloric acid to the acid, which crystallized on addition of hexane. Filtration gave racemic-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]methylacetic acid, mp 123°-126°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=[O:12])[C@@:5]1([CH3:27])[C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([CH:24]([CH3:26])[CH3:25])[CH:16]=1.COC[C@H]1[C@H](/C=C/C(/C)=C/C(OCC)=O)[C@@]1(C)C1C=C(C(C)C)C=C(C(C)C)C=1>>[CH3:1][O:2][CH2:3][C@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=[O:12])[C@@:5]1([CH3:27])[C:15]1[CH:16]=[C:17]([CH:24]([CH3:25])[CH3:26])[CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:20]=1
Reactant: COC[C@@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@H](COC)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: COC[C@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 47 %

Procedure:
Following a procedure similar to that for the preparation of Compound 28 but using Compound 26a as the starting material afforded the title compound (8 mg, 47% yield) as a white solid:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>CN(C=O)C.O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][CH:10]=1
Reactant: COCCO
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 66.6 %

Procedure:
2-Methoxyethanol (5.0 g) was added to a stirred suspension of sodium hydride (2.64 g of a 60% mineral oil suspension) in DMF (200 ml) at ambient temperature and under an atmosphere of argon. The stirred mixture was heated to 60° C. and then cooled to 5° C. Solid 4-bromobenzyl bromide (15 g) was added in one portion. The mixture was stirred for 12 hours at ambient temperature, then for 1 hour at 60° C. and cooled. The mixture was diluted with iced water (600 ml) and extracted with ethyl acetate (3×200 ml). The ethyl acetate extracts were combined, washed with 2M aqueous hydrochloric acid (100 ml), water (2×100 ml), saturated brine (100 ml), dried (MgSO4) and evaporated. The residue, an oil, was distilled using a short path distillation apparatus (furnace temperature 125° C./0.05 bar) to give 1-(4-bromobenzyloxy)-2-methoxyethane (9.8 g); NMR (CDCl3): 3.39(3H,s), 3.51(4H,m), 4.51(2H,s), 7.21(2H,d) and 7.44(2H,d).
Reaction SMILES: O=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.[NH2:17][OH:18].C[O-].[Na+].CCOCC>CO>[OH:18][N:17]=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)CCC(=O)CCc1ccccc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=C(O)CCC(CCc1ccccc1)=NO
Yield: 89.7 %

Procedure:
The ketone 99 (3.0 g, 13.6 mmol) and hydroxylamine hydrochloride (1.98 g, 27 mmol) were dissolved in methanol (20 mL) then sodium methoxide (2.9 g) was added. The solution was stirred and refluxed for 2 hr then cooled. Ether was added and the organic layer was washed twice with 2M HCl, brine and dried over MgSO4. Removal of solvent gave the oximes 100 (2.7 g 90%) as a mixture of E:Z isomers in the ratio 1.5:1.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH:2]1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[N:13][C:14]([NH2:15])=[C:9]2[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][C:17]=2[F:29])=[N:7]1.[C:30]([CH2:32][C:33](O)=[O:34])#[N:31].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[NH2:15][C:14]1[N:13]=[CH:12][N:11]=[C:10]2[N:6]([CH2:5][CH:2]3[CH2:3][CH2:4][N:1]3[C:33](=[O:34])[CH2:32][C:30]#[N:31])[N:7]=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:18][C:17]=3[F:29])[C:9]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2CC1CCN1
Reactant: N#CCC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Product: N#CCC(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a mixture of 1-(azetidin-2-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (236.4 mg, 0.610 mmol), 2-cyanoacetic acid (77.2 mg, 0.910 mmol) in DCM (8 mL) in ice bath, was added T3P (0.36 mL, 1.21 mmol) and TEA (0.34 mL, 2.42 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was loaded onto the silica gel column, purified with 0-3% gradient MeOH:CH2CL2, to get 3-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidin-1-yl]-3-oxo-propanenitrile (201 mg) as yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5](=[O:14])[CH:4]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+].O>CN(C)C=O>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:2][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]([CH3:13])[C:5](=[O:14])[CH:4]=3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: Cn1c(=O)cc(CBr)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)cc(CN2CCC(c3c[nH]c4ccccc34)CC2)c2ccccc21
Yield: 64.6 %

Procedure:
A suspension of 4-bromomethyl-l-methyl-2(1H)-quinolinone (756 mg, 3 mmol), 3-(4-piperidinyl)-1H-indole (600 mg, 3 mmol) and sodium hydrogencarbonate (378 mg, 4.5 mmol) in dry dimethylformamide (5 ml) was allowed to react at 80 ° C. for 2 hours. The reaction mixture was poured into water and the separated solid was filtered off. The solid was washed with water, dried and then recrystallized from methanol/tetrahydrofuran to give the desired product (III16) (720 mg, yield 65%). Mp 228°-229 ° C. (methanol/tetrahydrofuran).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:13])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1.Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>O>[CH2:15]([C:6]1[C:7]([CH3:12])=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[CH3:13])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Cc1cc(C)cc(C)c1
Reactant: CCCCCCCCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CCCCCCCCc1c(C)cc(C)cc1C
Yield: 34.7 %

Procedure:
A 750 ml flask is charged with 6.7 g (50 mmol) of anhydrous aluminium chloride and 120.2 g (1 mol) of mesitylene. 148.7 g (1 mol) of 1-chloroctane are added dropwise to this mixture over 2 h at room temperature. HCl gas slowly evolves. The dark orange emulsion is stirred for c. 30 h at room temperature and then poured into water and extracted with toluene. The organic phase is isolated and concentrated on a rotary evaporator. The resultant oil is fractionated under vacuum to give, at 88°-92° C. and 1.8 mbar, 80.6 g of the title product as a colourless liquid. Gas chromatography (GC) and 1H-NMR spectrum analysis show that mono-n-octylmesitylene is obtained in 90% purity. The distillation residue contains mainly dioctylmesitylene.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=2)[C:4](=O)[NH:3][CH:2]=1.P(Cl)(Cl)([Cl:25])=O>CN(C)C1C=CC=CC=1>[Cl:25][C:4]1[C:5]([CH2:7][CH2:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=2)=[CH:6][N:1]=[CH:2][N:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2cnc[nH]c2=O)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(CCc2cncnc2Cl)cc1
Temperature: 100 °C
Yield: 78.5 %

Procedure:
tert-Butyl 4-[2-(pyrimidin-4(3 H)-on-5-yl)ethyl]benzoate (0.6 g,) was dissolved in N,N-dimethylaniline (5 ml) and treated with phosphorous-oxy-chloride (1.53 g 10 mmol). The reaction was heated to 100° C. for 2.5 hours and then evaporated at reduced pressure. The residue was diluted with EtOAc, washed (1N HCl 2×, H2O, saturated brine), dried over MgSO4 and evaporated to give tert-butyl 4-[2-(4-chloropyrimidin-5-yl)ethyl]benzoate as a brown oil (0.5 g, 64%) which was used without further purification.