Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2].[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>N1C=CC=CC=1>[C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:25](=[O:28])[CH2:26][CH3:27])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2]
Reactant: CCC(=O)Cl
Reactant: N#CC=C1CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Solvent: c1ccncc1
Product: CCC(=O)NC[C@H]1CN(c2ccc(N3CCC(=CC#N)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
The mixture of (S)-N-{3-[4-(4-cyanomethylidene-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine (1.5 mmol), propionyl chloride (1.79 mmol) in 10 ml pyridine was stirred at room temperature for 3 hours. Evaporation of the solvent under vacuum and silica gel column chromatography afforded the titled compound in 52% yield.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:26])=[C:16]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:17]=3F)[C:12](=[O:27])[C:11]([C:28]([OH:30])=[O:29])=[CH:10]2)[CH2:8][CH2:7]1>C(O)C>[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:26])=[C:16]([N:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)[C:17]=3[O:1][CH2:2][CH3:3])[C:12](=[O:27])[C:11]([C:28]([OH:30])=[O:29])=[CH:10]2)[CH2:7][CH2:8]1
Reactant: CC[O-]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 52 h

Procedure:
To a solution of sodium ethoxide prepare from sodium (0.75 g) and absolute ethanol (30 ml) was added 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (0.8 g) and the mixture in sealed tube was stirred for 52 hours at 140° to 150° C. and then concentrated. Water (60 ml) was added to the residue, and the solution was adjusted pH 7 with acetic acid and and extracted with chloroform. The chloroform layer was washed with saturated saline solution, dried over anhydrous sodium sulfate and then concentrated. The resulting residue was purified by silica gel column chromatography eluting with chloroform-methanol (2:1)→chloroform-methanol-concentrated aqueous ammonia (20:6:1→10:10:1) and recrystallized from ethanol to give the title compound (75 mg) as light brown prisms, mp 119°-122° C.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[C:19]([C:31]2[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=2)[N:20]3C2CCCCO2)[CH2:11]1)(C(C)(C)C)(C)C.O.CC(O)=O>C1COCC1>[C:31]1([C:19]2[NH:20][C:21]3[C:17]([N:18]=2)=[C:16]([O:15][C@H:12]2[CH2:13][CH2:14][C@H:10]([CH2:9][OH:8])[CH2:11]2)[N:24]=[CH:23][N:22]=3)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@H](Oc2ncnc3c2nc(-c2cccc4ccccc24)n3C2CCCCO2)C1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@H](Oc2ncnc3[nH]c(-c4cccc5ccccc45)nc23)C1
Reaction time: 7 h
Yield: 84.7 %

Procedure:
To a stirred solution of 6-{[(1S,3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentyl]oxy}-8-(1-naphthyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (156.9 mg, 0.0002808 mol) in THF (3.8 mL) was added water (3.8 mL) and AcOH (7.6 mL), and the reaction mixture was stirred for 7 hours. The reaction mixture was quenched by the slow addition of saturated NaHCO3, and the resulting mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 5% MeOH/CH2Cl2) to obtain 85.7 mg (85%) of the title compound as a white solid. LC/MS: Rt=1.51 min, ES+ 361 (FA standard).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:13]([CH3:16])(=[O:15])=[O:14])=[N:6][CH:7]=1.[Cl:17][CH:18]([Cl:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][CH:25]=1)=[O:20].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1CCCC1=O>[Cl:17][CH:18]([Cl:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:7]=[N:6][C:5]([CH:8]3[CH2:12][CH2:11][CH2:10][N:9]3[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][CH:3]=2)=[CH:28][CH:29]=1)=[O:20]
Reactant: CS(=O)(=O)N1CCCC1c1ccc(Br)cn1
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)N1CCCC1c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Temperature: 80 °C
Yield: 19.9 %

Procedure:
A mixture of 5-bromo-2-(1-(methylsulfonyl)pyrrolidin-2-yl)pyridine (100 mg, 0.328 mmol), 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)-phenyl)-propan-2-yl)acetamide (145 mg, 0.328 mmol) and tris(2-furyl)phosphine (15.5 mg, 0.066 mmol) is dissolved in N-methylpyrrolidinone (1.6 mL) and deoxygenated. Tris(dibenzyliden-eacetone) dipalladium(0) (30.5 mg, 0.033 mmol) is then added and the mixture is heated to 80° C. overnight. The mixture is then cooled and purified by preparative hplc (Prep HPLC=Waters, Column=Gemini NX C18 21×150 mm 5 um, MP A=0.1% trifluoroacetic acid in water MP B=acetonitrile, Gradient 10% B to 50% in 10 min holding for 2 min, 20 mL/min.) Fractions are dried on rotovap and freeze-dried with 1,4-dioxane to give the title compound (33 mg): 1H NMR (400 MHz, DMSO-d6) 1.9-2.0 (m, 2H), 2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.0 (s, 3H), 3.5-3.6 (m, 2H), 4.15-4.35 (m, 1.5H), 4.45 (t, 0.5H), 4.55-4.65 (m, 0.5H), 4.7-4.75 (m, 0.5H), 4.9-5.0 (m, 2H), 6.5 (s, 1H), 7.5 (d, 2H), 7.65 (d, 1H), 7.75 (d, 2H), 8.2 (dd, 1H), 8.6 (d, 1H), 8.85 (d, 1H). m/z (CI) M+H 504+506.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:43]1([C@H:49]([NH:56][CH3:57])[CH2:50][N:51]2[CH2:54][CH:53]([OH:55])[CH2:52]2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:56]([C@@H:49]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:50][N:51]2[CH2:52][CH:53]([OH:55])[CH2:54]2)[CH3:57])=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: CN[C@H](CN1CC(O)C1)C1CCCCC1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)c1ccc(C#N)cc1)[C@H](CN1CC(O)C1)C1CCCCC1
Reaction time: 0.17 h
Yield: 49 %

Procedure:
4-cyanobenzoic acid (65.0 mg, 0.44 mmol) in DCM (2 mL) was treated with DIPEA (0.231 mL, 1.32 mmol) and TBTU (142 mg, 0.44 mmol) and the suspension was stirred for 10 min. A 125 mg/mL solution of (S)-1-(2-cyclohexyl-2-(methylamino)ethyl)azetidin-3-ol (Compound G2.3) (125 mg, 0.44 mmol) in DCM (1 mL) was added and the reaction was stirred at ambient temperature overnight. The reaction was washed with 8% aq. sol. of NaHCO3 and concentrated. The residue was dissolved in DMSO (0.4 mL) and filtered through a syringe filter. The residue was purified by HPLC to give the title compound (73.6 mg, 49%). Mixture of rotamers. 1H NMR (600 MHz, DMSO-d6) δ 0.53-0.70, 0.89-1.81, 2.43-2.59, 2.64-2.78, 3.03, 3.28-3.31, 3.43-3.54, 4.11-4.30, 5.23, 5.26, 7.48, 7.61, 7.87-7.94. HRMS (M+H)+: calculated 342.2181. found 342.2193
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([OH:29])[C:26]3[C:21](=[CH:22][C:23]([CH3:30])=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:32]([O:39][C:40](=[O:44])[C@H:41]([CH3:43])O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][C@@H:41]([C:40]([O:39][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:44])[CH3:43])[C:26]3[C:21](=[CH:22][C:23]([CH3:30])=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O[C@H](C)C(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6 g 4-{2-[(4-Hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester and 2.5 g benzyl-L-lactate in 97 ml THF were added 5.5 g triphenylphosphine and 3.6 g diethylazodicarboxylate. After stirring for 16 h at RT LCMS indicated complete conversion and water was added to the reaction mixture which was then extracted with ethyl acetate. The residue obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 5.5 g
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#N)=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-:17].[Na+].[Na+].O.[CH2:23]([OH:25])[CH3:24]>C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([O:25][CH2:23][CH3:24])=[O:17])=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCO
Reactant: Cc1cnc(N)c(C#N)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(C)cnc1N
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 2-amino-5-methylpyridine-3-carbonitrile (353 mg) in ethanol (10 mL) was added concentrated sulfuric acid (5 ml), and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was added dropwise to a mixture of sodium carbonate (10.6 g), water (50 mL) and ethyl acetate (50 mL) under ice-cooling with stirring. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (373 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.Cl.[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][CH2:27]2.C([N:37](C(C)C)CC)(C)C>C(Cl)Cl>[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[CH:28]([NH:37][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:12][C:11]=13)=[O:19])[CH2:27]2
Reactant: CCN(C(C)C)C(C)C
Reactant: C1CN2CCC1CC2
Reactant: O=C(O)c1cccc2oc(-c3ccc(Cl)cc3)nc12
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(Cl)cc3)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.5 %

Procedure:
A 25 mL round bottomed flask equipped with a reflux condenser was purged with nitrogen and charged with 2-(4-chlorophenyl)benzoxazole-4-carboxylic acid (0.050 g, 0.18 mmol) followed by thionyl chloride (5 mL). The resulting suspension was heated to reflux for 1 hr, after which time a light yellow solution was obtained. The reaction was then cooled and the thionyl chloride removed under reduced pressure affording an off-white solid. This solid was dissolved in methylene chloride (10 mL) and quinuclidine dihydrochloride (0.056 g, 0.27 mmol) added followed by the drop-wise addition of diisopropylethylamine (0.371 g, 2.87 mmol) over 5 min. After stirring at room temperature for 3 hrs the reaction was quenched by the addition of water (10 mL) and the organic layer separated. Subsequent washing of the organic layer with water (10 mL) followed by brine (10 mL), drying over MgSO4, filtration and concentration afforded a tan solid. This solid was purified by preparative HPLC to afford 0.012 g (17% yield) of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-chlorophenyl)benzoxazole-4-carboxamide as an white solid: mp 194-196° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.13 (m, 1H), 8.23 (dd, J=6.7, 1.9 Hz, 2H), 8.03 (dd, J=8.2, 0.9 Hz, 1H), 7.97 (dd, J=7.7, 0.9 Hz, 1H), 7.78 (dd, J=6.7, 1.9 Hz, 2H), 7.58 (t, J=8.0 Hz, 1H), 4.09 (m, 1H), 3.28 (m, 1H), 2.85 (m, 2H), 2.75 (m, 2H), 2.63 (m, 1H), 2.08 (m, 1H), 1.99 (m, 1H), 1.65 (m, 2H), 1.57 (m, 1H); MS (ESI) m/z 382 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH2:18])[CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[C:21](=[O:39])[N:22]([C:27]2[CH:28]=[C:29]([CH:34]=[C:35]([F:38])[C:36]=2[CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:23]=[C:24]([Br:26])[N:25]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1.Cl>[Br:26][C:24]1[N:25]=[C:20]([NH:18][C:15]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:17][CH2:16]2)[C:21](=[O:39])[N:22]([C:27]2[CH:28]=[C:29]([CH:34]=[C:35]([F:38])[C:36]=2[CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:23]=1
Reactant: NC1(c2ccccc2OCc2ccccc2)CC1
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(Br)c2=O)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC3(c4ccccc4OCc4ccccc4)CC3)c2=O)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 1-(2-(benzyloxy)phenyl)cyclopropanamine (Example 167a, 5 g) in dioxane (200 mL) was treated with 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-5-fluoro-4-methyl-benzoic acid, methyl ester (Example 252g, 7.5 g) and N-ethyldiisopropylamine (5.36 mL) under nitrogen. The resulting solution was stirred at 100° C. for 8 h. The cooled reaction mixture was diluted with 2M HCl (300 mL), and extracted with ether (3×300 mL). The combined organics were dried (MgSO4), filtered and evaporated to afford crude product. Purification (SiO2 chromatography eluting with 20% ethyl acetate in iso-hexane) gave the subtitle compound. (9.20 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[CH3:8][O:9][CH2:10][CH2:11][Br:12]>>[BrH:12].[CH3:8][O:9][CH2:10][CH2:11][N:3]1[C:2]([CH3:1])=[CH:6][S:5][C:4]1=[NH:7]
Reactant: COCCBr
Reactant: Cc1csc(N)n1
Product: Br
Product: COCCn1c(C)csc1=N
Temperature: 85 °C
Yield: 34 %

Procedure:
A mixture of 4-methylthiazol-2-ylamine (0.75 g, 6.5 mmol) and 2-bromoethyl methyl ether (730 μL, 7.8 mmol) was heated at 85° C. for 15 hours. The mixture was cooled to ambient temperature and the resulting solid was triturated with isopropanol. Recrystallization from hot ethanol afforded 0.56 g (34%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ ppm 2.25 (d, J=1.4 Hz, 3H) 3.25 (s, 3H) 3.57 (t, J=5.1 Hz, 2H) 4.15 (t, J=5.1 Hz, 2H) 6.68 (d, J=1.4 Hz, 1H) 9.40 (s, 1H); MS (DCI/NH3) m/z 173 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH:20]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:23].[Na+]>O1CCOCC1.O.C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH:20]=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(C)nc2c(OCc3ccccc3)cccc12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cc(C=O)c2cccc(OCc3ccccc3)c2n1
Reaction time: 8 h
Yield: 61.1 %

Procedure:
To a stirred solution of 8-benzyloxy-2-methyl-4-vinylquinoline (200 mg) in 1,4-dioxane-water (3:1, V/V, 1 ml) was added catalytic amount of osmium tetroxide in tert-butanol in an ice bath. Sodium periodate (342 mg) was added to the reaction mixture portionwise and the resulting suspension was vigorously stirred overnight at ambient temperature. The mixture was extracted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give a brown oil. This was purified by a silica gel column eluting with ethyl acetate-n-hexane (1:3, V/V) to give 8-benzyloxy-4-formyl-2-methylquinoline as a yellow solid (123 mg).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([OH:40])[CH2:19][CH:20]([OH:39])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(O[CH:44](OCC)[CH2:45][CH2:46]Cl)C.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=[CH:66][NH+:65]=[CH:64]C=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:17]([CH:18]1[CH2:19][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[O:39][CH:44]([CH2:45][CH2:46][N:65]([CH3:66])[CH3:64])[O:40]1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8]/[CH:7]=[CH:6]\[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CC(O)CCCCCCC/C=C\C/C=C\CCCCC
Reactant: c1cc[nH+]cc1
Reactant: CCOC(CCCl)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1CC(CCCCCCC/C=C\C/C=C\CCCCC)OC(CCN(C)C)O1
Temperature: 80 °C
Yield: 457.9 %

Procedure:
A solution of the diol (6Z,9Z,29Z,32Z)-octatriaconta-6,9,29,32-tetraene-18,20-diol (7) (940 mg, 1.68 mmol) and 3-chloropropionaldehyde diethylacetal (563 μL, 3.36 mmol) in toluene (15 mL) was treated with PPTS (50 mg) and heated (80° C., 2 h). After cooling (rt) the reaction mixture was poured into sat. aq. NaHCO3, extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in a solution of (CH3)2NH (25 mL, 5.6M in EtOH), transferred to a sealed reaction vessel and heated (80° C., 16 h). Once complete the yellow solution was concentrated and the residue was subjected to chromatography (100% EtOAc) to yield 2-(4-((8Z,11Z)-heptadeca-8,11-dien-1-yl)-6-((9Z,12Z)-octadeca-9,12-dien-1-yl)-1,3-dioxan-2-yl)-N,N-dimethylethanamine (8) (585 mg, 54% over 2 steps) as a pale yellow oil. Rf 0.5 (10% CH3OH—CH2Cl2); 1H NMR (400 MHz, CDCl3) 5.46-5.29 (m, 8H), 4.85 (t, 0.5H), 4.59 (t, 0.5H), 4.08-3.98 (m, 0.5H), 3.80-3.70 (m, 0.5H), 3.60-3.50 (m, 1H), 2.78 (app. t, 4H), 2.50-2.37 (m, 2H), 2.32-2.21 (m, 6H), 2.13-2.02 (m, 8H), 1.88-1.72 (m, 2H), 1.63-1.22 (m, 40H), 0.91 (t, 6H). FW 643.47, C43H79NO2.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>CN(C)C=O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:16][CH2:15][CH2:14][O:13][CH3:12])[N:10]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: COCCN
Solvent: CN(C)C=O
Product: COCCNc1nc(Cl)ccc1C(N)=O
Temperature: 60 °C
Yield: 64 %

Procedure:
Refer to synthesis of D46 for preparation of 2,6-dichloro-nicotinamide (1). A sealed reaction vessel containing 2,6-dichloro-nicotinamide (1) (8.66 g, 45.3 mmol) and 2-methoxy-ethylamine (15.6 mL, 181 mmol) in anhydrous dimethylformamide (40 mL) was heated to 60° C. for 7 h. The reaction was then cooled to room temperature. Dimethylformamide was azeotropically removed by the addition and evaporation of toluene (6×700 mL) by rotary evaporation with water bath at 70° C. An orange oil was obtained (12.2 g). The oil was fractionated by dry-pack column chromatography as follows: the oil was diluted with CH2Cl2 (400 mL) followed by the addition of silica gel (100 g, 230-400 mesh) and concentrated to dryness. This was loaded onto a silica column (200 g, 230-400 mesh) and eluted with 50% EtOAc/hexanes. Pure fractions were combined and concentrated to give the title compound as a white solid (5.37 g, 64% isolated yield). 1H NMR 400 MHz (d6-DMSO) δ 7.79 (d, J=7.8 Hz, 1H), 7.30 (s, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 4.04 (br t, J=4.7 Hz, 1H), 3.80 (td, J=5.5, 4.7 Hz, 2H), 3.63 (t, J=5.5 Hz, 2H), 2.94 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Li]C(CC)C.[S].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:19]=1[C:20]#[N:21].C[S:28](C)=O>C(=O)=O.CC(C)=O.O.C1COCC1>[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([S:28][C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[CH:3]=2)[C:19]=1[C:20]#[N:21]
Reactant: N#Cc1c(F)cccc1F
Reactant: COc1cc(C)cc(Br)c1
Reactant: CS(C)=O
Agent: O=C=O
Agent: [Li]C(C)CC
Agent: [S]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C)cc(Sc2cccc(F)c2C#N)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 1 g (0.005 mol) of 3-bromo-5-methoxytoluene in 10 mL of freshly distilled THF was cooled in dry ice/acetone and stirred under a N2 atmosphere. To this was added dropwise via a syringe 8.46 mL (0.011 mol) of sec-BuLi (1.3M in cyclohexane). The resultant mixture was stirred for 10 min after which 0.19 g of elemental sulfur was added in one portion. The reaction mixture was brought to room temperature and left stirring for 12 h. The mixture was cooled in ice/water bath. 0.69 g (0.005 mol) of 2,6-difluorobenzonitrile in 5 mL of dry DMSO was added. After sitting for 20 min, the mixture was poured into water (100 mL) and extracted with 3×50 mL of EtOAc. The EtOAc solution was washed with 1N NaOH, water, and dried over MgSO4Removal of EtOAc under vacuo resulted in a crude product which was chromatographed on silica gel (flash; EtOAc/Hexane 1:9). This resulted in 0.63 g (46%) of 2-fluoro-6-[(3-methyl-5-methoxyphenyl)thio]benzonitrile: mp 94°-95° C.; NMR (Me2SO-d6, 200 MHz) δ 2.28 (s, 3H), 3.7 (s, 3H), 6.8-7 (m, 4H), 7.34 (apparent d, 1H), 7.62 (dd, 1H). Anal. Calc. for C15H12NOSF: C, 65.92; H, 4.43; N, 5.12; S, 11.73. Found: C, 66.03; H, 4.49; N, 5.09; S, 11.8.
Reaction SMILES: [O:1]([CH2:8][CH2:9]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl>[O:1]([CH2:8][CH2:9][Cl:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOc1ccccc1
Reactant: O=S(Cl)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Product: ClCCOc1ccccc1

Procedure:
2-phenoxy-ethanol is reacted with thionyl chloride in the presence of benzyl-trimethyl ammonium chloride in a weight ratio of alcohol to tetra-alkyl-ammonium chloride of 28:1 respectively, in dichloromethane as a solvent, at a temp. of from about 10° C. to 50° C. to form 2-phenoxy ethyl chloride;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[N:14][C:15]=2[NH:17][CH2:18][C@@H:19]([OH:21])[CH3:20])[NH:10][N:9]=1.[P:31]([O:36]C)([O:34][CH3:35])[O:32][CH3:33].C(Br)(Br)(Br)Br.Cl>N1C=CC=CC=1>[CH3:33][O:32][P:31](=[O:36])([O:34][CH3:35])[O:21][CH:19]([CH3:20])[CH2:18][NH:17][C:15]1[N:14]=[C:13]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[N:12]=[C:11]2[NH:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:16]=12
Reactant: C[C@H](O)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(-c3ccccc3Cl)c12
Reactant: COP(OC)OC
Agent: BrC(Br)(Br)Br
Agent: Cl
Solvent: c1ccncc1
Product: COP(=O)(OC)OC(C)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(-c3ccccc3Cl)c12
Temperature: 0 °C

Procedure:
(S)-1-[3-(2-chlorophenyl)-6-(2,4-difluorophenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]propan-2-ol (2.5 g, 5.79 mmol) was dissolved in 20 mL pyridine at room temperature, and the mixture was cooled to 0° C. with stirring. P(OCH3)3 (1.93 mL, excess) and CBr4 (0.96 g) were added slowly, and the reaction mixture was allowed to warm up to room temperature over 20 minutes with stirring. The reaction mixture was poured into cold 1N HCl, and the resulting solution was extracted with EtOAc. The combined organic layers were washed with 1N HCl, followed by saturated aqueous NaHCO3, then with saturated brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 30%-60% EtOAc in methylene chloride) to give 3.132 g of phosphoric acid 2-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-1-methyl-ethyl ester dimethyl ester, MS (M+H)=540.