Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.[C:12]1([C@@H:18]([NH:20][C:21]2[N:26]=[C:25](Cl)[CH:24]=[C:23]([Cl:28])[N:22]=2)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[C:12]1([C@@H:18]([NH:20][C:21]2[N:26]=[C:25]([N:3]3[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[N:5]=[CH:4]3)[CH:24]=[C:23]([Cl:28])[N:22]=2)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(Cl)cc(-n2cnc3ccccc32)n1)c1ccccc1
Temperature: 0 °C
Yield: 61.4 %

Procedure:
To a suspension of NaH (74 mg) in DMF (5 mL) at 0° C. was added benzimidazole (204 mg). The reaction mixture was stirred at 0° C. until gas evolution ceased, then stirred at room temperature until the mixture became homogeneous (ca. 10 min.). A solution of 2-[(S)-1-phenylethylamino]-4,6-dichloropyrimidine (412 mg) in DMF (2 mL) was added to the mixture, which was then placed in 100° C. oil bath for 1 h. The reaction mixture was cooled and carefully quenched with water. The layers were separated, and the aqueous layer was extracted CH2Cl2 (2×15 mL). Combined organic layers was washed with water and brine and dried over anhydrous Na2SO4. The solvent was concentrated under reduced pressure, and the crude product was purified by flash chromatography (1:5 EtOAc:hexanes) to give 330 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.21 (br s, 1H); 7.82 (d, J=7.5 Hz, 1H); 7.75 (br s, 1H); 7.45-7.28 (m, 7H); 6.8 (s, 1H); 5.92 (br s, 1H); 5.2 (br s, 1H); 1.62 (d, J=7.1 Hz, 3H). Mass spectrum (CI) 350.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([CH3:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]([O:20][CH3:21])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:29][CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: COC(=O)c1cc2c(C)cccc2n1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc2c(CBr)cccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A solution of methyl 1-tert-butoxycarbonyl-4-methylindole-2-carboxylate (0.13 g, 0.48 mmol), NBS (0.087 g, 0.48 mmol), and AIBN (4 mg, 0.024 mmol) in carbon tetrachloride (1.9 mL) was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and filtered and washed with carbon tetrachloride. The filtrate was evaporated to give a yellow oil that was purified by silica gel chromatography (EtOAc:hexane=8:92) to give 0.12 g (72% yield) of the title compound as a pale yellow solid:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13]C)=[O:12])=[O:7])(=[O:4])=[O:3].[OH-].[Na+]>CO.O>[CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([OH:13])=[O:12])=[O:7])(=[O:4])=[O:3]
Reactant: COC(=O)c1cccc(C(=O)NS(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)NC(=O)c1cccc(C(=O)O)c1
Yield: 41.2 %

Procedure:
Methyl 3-(methylsulfonylcarbamoyl)benzoate (700 mg, 2.72 mmol) was dissolved in methanol at 25° C. with stirring then 1.0 N NaOH (5.56 mL, 5.56 mmol) was added. The reaction mixture was stirred for 20 hours, diluted with water, and the methanol removed in vacuo. The aqueous was washed with diethyl ether (2×) then acidified to pH=3 with 1N HCl. The resulting solution was extracted with ethyl acetate to give 3-(methylsulfonylcarbamoyl)benzoic acid (285 mg, 1.12 mmol, 42% yield). MS found: (M+H)+=244.00.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:21][CH2:22][N:23]=[C:24]=[N:25][CH2:26][CH2:27][CH2:28][N:29](C)C.Cl.NCCCN1C=CN=C1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:29][CH2:28][CH2:27][CH2:26][N:25]2[CH:21]=[CH:22][N:23]=[CH:24]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cccc(Cl)n1
Agent: Cl
Agent: NCCCn1ccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCCCn1ccnc1)c1cccc(Cl)n1
Reaction time: 18 h
Yield: 62.5 %

Procedure:
6-Chloro-pyridine-2-carboxylic acid (1.00 g, 6.35 mmol) was dissolved in DCM (20 mL) and HOBt (1.03 g, 7.62 mmol), EDC.HCl (1.46 g, 7.62 mmol) and 1-(3-aminopropyl)imidazole (0.95 g, 7.62 mmol) were added. The reaction mixture was stirred for 18 h, diluted with DCM (130 mL) washed with sat aq Na2CO3 (100 mL), brine (30 mL), water (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was triturated with water to give the crude title compound (1.05 g, 63%) as an off-white solid. LCMS (ES+): 266 [MH]+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1ccc(F)cc1)N1CCN(C2CCCC2)CC1
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 4-fluorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (34%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2=[C:7]([OH:12])[CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[O:4][CH2:3]1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.C(OCC)(=O)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([O:12][C:7]2[C:6]3[C:2]([CH3:13])([CH3:1])[CH2:3][O:4][C:5]=3[C:10]([CH3:11])=[CH:9][CH:8]=2)=[N:16][CH:17]=1)([O-:23])=[O:22]
Reactant: Cc1ccc(O)c2c1OCC2(C)C
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c2c1OCC2(C)C
Temperature: 60 °C
Yield: 61.3 %

Procedure:
3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-ol (Intermediate 184, 0.9 g, 5.0 mmol) was dissolved in CH3CN (5 mL) in the presence of 2-chloro-5-nitropyridine (790 mg, 5.0 mmol) and K2CO3 (1.72 g, 12.5 mmol) and the resulting suspension was heated to 60° C. for 1.5 hrs. The mixture was then cooled to room temperature and diluted with water and ethyl acetate. Two phases were separated and the organic layer was washed with brine, then dried over Na2SO4 and evaporated to dryness, The residue was purified by flash chromatography on silica gel using cyclohexane to cyclohexane/ethyl acetate 90:10 as eluents affording the title compound (0.92 g) as yellowish solid.
Reaction SMILES: OO[S:3]([O-:5])=[O:4].[K+].[OH:7][CH:8]1[CH2:13][CH:12]([CH2:14][CH2:15][CH3:16])S[C:10]2[S:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:9]1=2>O.CO>[OH:7][CH:8]1[CH2:13][CH:12]([CH2:14][CH2:15][CH3:16])[S:3](=[O:5])(=[O:4])[C:10]2[S:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:9]1=2
Reactant: O=S([O-])OO
Reactant: CCCC1CC(O)c2cc(S(N)(=O)=O)sc2S1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCC1CC(O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of "oxone"® (196.7 g, 0.32 mol) in water (870 ml) was added to a stirred solution of 5 (56.6 g, 0.19 mol) in methanol (870 ml) over 45 minutes. After stirring at ambient temperature for 20 hours, the mixture was filtered and the solid washed with methanol. The combined filtrate and washings were concentrated in vacuo below 50° C. to remove methanol. The aqueous suspension was extracted with ethyl acetate (1000 ml and 2×600 ml), the combined extracts were washed twice with water, dried over sodium sulfate and evaporated in vacuo to yield 47.37 g of 6.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH3:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1.[OH:23]C1C(OC)=CC=CC=1C(=O)C>>[OH:23][C:7]1[CH:2]=[CH:3][C:4]2[O:21][CH:9]3[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][CH2:13][C:8]3([CH3:22])[C:5]=2[CH:6]=1
Reactant: COc1cccc(C(C)=O)c1O
Reactant: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(O)cc3OC2C1
Product: CC(C)(C)OC(=O)N1CCC2(C)c3cc(O)ccc3OC2C1

Procedure:
Synthesized as described for tert-butyl 7-hydroxy-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate and as described in J. Med. Chem., 1989, 32, 2221-2226 starting from 1-(2-hydroxy-3-methoxyphenyl)-ethanone. MS m/z 250 [M-tBu+H]+
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1CCCC1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23](O)[CH:22]=1>CO>[F:20][C:21]1[CH:26]=[C:25]2[C:24]([C:27](=[O:29])[CH2:28][C:2]3([O:1]2)[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1ccc(F)cc1O
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccc(F)cc1O2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 21.4 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (7.5 g, 37.8 mmol) in pyrrolidine (4.5 mL, 54.1 mmol) and anhydrous methanol (10.2 mL) was added 1-(4-fluoro-2-hydroxy-phenyl)ethanone (5.8 g, 37.6 mmol). The reaction mixture was stirred at 80° C. for 2.5 hours. The methanol was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate (150 mL), washed with 1N HCl (1×150 mL) and brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a yellow oil. The oil was diluted with hexanes (400 mL) and was heated at 60° C. until in solution. Once dissolved, the solution was allowed to cool to 25° C. The crystals were collected via vacuum filtration, rinsing with hexanes to remove tert-butyl 4-oxo-7-pyrrolidin-1-yl-spiro[chromane-2,4′-piperidine]-1′-carboxylate (8.6 g), which was collected as light yellow solid; ESI-MS m/z calc. 386.2. found 387.2 (M+1)+; Retention time: 2.59 minutes (3 min run). The filtrate was concentrated and the residue was subjected to column chromatography (0-100% ethyl acetate/hexanes) to give tert-butyl 7-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (2.7 g, 21%) as a light yellow solid; ESI-MS m/z calc. 335.2. found 336.2 (M+1)+; Retention time: 2.49 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J=8.6, 6.7 Hz, 1H), 6.80-6.62 (m, 2H), 3.88 (d, J=12.1 Hz, 2H), 3.21 (t, J=12.0 Hz, 2H), 2.71 (s, 2H), 2.02 (d, J=12.8 Hz, 2H), 1.62 (td, J=14.1, 4.8 Hz, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]2[S:13]C(=O)[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([SH:13])=[C:11]([OH:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1oc2cc(OCc3ccccc3)ccc2s1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Oc1cc(OCc2ccccc2)ccc1S
Temperature: 80 °C
Yield: 81.3 %

Procedure:
Dissolve 6-benzyloxy-benzo[1,3]oxathiol-2-one (24.33 g, 94.29 mmol) in dioxane (1000 mL) and add a KOH solution (94.29 mL, 188 mmol, 2M in water) with stirring. Flush the flask with N2 and then heat the reaction mixture to 80° C. for 2 hours. Cool the reaction mixture to room temperature and remove the solvent under reduced pressure. Adjust the pH to <2 with HCl (200 mL, 1.0 M in water). Extract the aqueous layer with EtOAc (3×500 mL). Combine the organic layers and dry with Na2SO4, filter and concentrate to give 17.8 g of 5-benzyloxy-2-mercapto-phenol (81.4%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][C:14]([NH:17][CH2:18][C:19]3([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:16]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][C:14]([NH:17][CH2:18][C:19]3([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:20][CH2:21][CH2:22]3)=[CH:15][CH:16]=2)=[CH:7][C:3]=1[C:4]([NH:30][CH2:31][CH2:32][NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:5]
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: O=C(O)c1cc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCNC(=O)c1cc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)ccc1F)OCc1ccccc1
Reaction time: 4 h
Yield: 50.2 %

Procedure:
To a 20 dram vial was added 2-fluoro-5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzoic acid (320 mg, 0.8 mmol, 1.0 equiv), benzyl 2-aminoethylcarbamate (242 mg, 1.0 mmol, 1.3 equiv), HOBt (141 mg, 1.0 mmol, 1.3 equiv), EDC HCl (200 mg, 1.0 mmol, 1.3 equiv), DIPEA (550 μL, 3.8 equiv) and CH2Cl2 (5 mL). The reaction was stirred for 4 h and then concentrated and then purified using a silica gel column (50%-100% EtOAc/hexanes) to afford 230 mg (50%) of benzyl 2-(2-fluoro-5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamido)ethylcarbamate as a white foam.
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](=[O:22])[CH:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[N+:2]=[N-:3].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([O:22][C:23]([CH3:24])=[O:25])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[N+:2]=[N-:3]
Reactant: CC(=O)OC(C)=O
Reactant: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)C(=O)CC12
Solvent: c1ccncc1
Product: CC(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(N=[N+]=[N-])C2C1

Procedure:
A solution of benzyl 6-azido-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (1 mmol) and acetic anhydride (10 mmol) in anhydrous pyridine (1 ml) is kept at 0°-5° C. for 3 days. The solution is concentrated under vacuum, diluted with ethyl acetate, washed with water, pH 2 buffer, 5% sodium bicarbonate solution, and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to give benzyl 6-azido-3-acetoxyl-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([CH2:12][OH:13])[CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].IC>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([CH2:12][O:13][CH3:14])[CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: OCC1CCc2c(Cl)ncnc2C1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COCC1CCc2c(Cl)ncnc2C1
Reaction time: 18 h
Yield: 35.3 %

Procedure:
To a slurry of (4-chloro-5,6,7,8-tetrahydroquinazolin-7-yl)methanol (reagent preparation 42, 0.80 g, 0.40 mmol), potassium carbonate (0.11 g, 0.81 mmol) and THF (15 mL) was added iodomethane (0.09 mL, 0.60 mmol). The reaction mixture was stirred for 18 hours and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography provided 4-chloro-7-(methoxymethyl)-5,6,7,8-tetrahydroquinazoline (0.03 g, 35% yield) as a waxy solid. MS (ES) for C10H13ClN2O: 213 (MH+).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:14]1(B(O)O)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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]>[CH:14]1([C:2]2[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:16][CH2:15]1
Reactant: O=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(C(F)(F)F)nc1C1CC1
Temperature: 90 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
2-Chloro-6-(trifluoromethyl)nicotinaldehyde (176 mg, 0.840 mmol), cyclopropylboronic acid (152 mg, 1.76 mmol), sodium carbonate (267 mg, 2.52 mmol) and tetrakis(triphenylphosphine)palladium (0) (48.5 mg, 0.0420 mmol) were combined, diluted with toluene (2 mL) and water (200 μL). The reaction vial was purged with argon, heated to 90° C. and stirred for 24 hours. The reaction was allowed to cool, loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to yield 2-cyclopropyl-6-(trifluoromethyl)nicotinaldehyde (130 mg, 0.604 mmol, 71.9% yield).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[CH2:21][NH2:22]>CC#N>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[CH2:21][NH:22][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NCc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cl)nc1NCc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a mixture of 2,6-dichloro-3-nitropyridine (1.0 g, 5.18 mmol) and potassium carbonate (848 mg, 6.14 mmol) in 15 mL MeCN was added 2,6-dichlorobenzylamine (0.63 mL, 5.18 mmol) at 0° C. The reaction mixture was stirred for one hour at 0° C. and then for 10 hours at room temperature. The organic solvent was evaporated and the residue was purified by silica gel chromatography (EtOAc:Hex=1:10) giving 16 [511 mg].
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(O[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:17]2[S:16][CH:15]=1)(=O)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@H:17]2[S:16][CH:15]=1
Reactant: Oc1cccc(O)c1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3ccc(O)cc3O)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
A solution of 0.055 g of resorcinol in 0.3 ml of trifluoracetic acid is mixed with 0.04 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and the solution is left to stand for 15 minutes at room temperature. It is diluted with an equal quantity of toluene and then evaporated to dryness under reduced pressure. 3-(2,4-Dihydroxybenzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid is obtained by working up the residue in accordance with the process indicated in example 6; this acid shows the following Rf values in a thin layer chromatogram (silica gel): 0.66 (system n-butanol/acetic acid/water, 75:7.5:21), 0.70 (system n-butanol/acetic acid/water, 67:10:23) and 0.52 (system n-butanol/ethanol/water, 40:10:50).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[N:23]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:22]=[N:21][CH:20]=4)=[CH:13][CH:12]=3)=[C:9]([CH3:32])[N:8]([C@@H:33]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O>>[C:26]([O:25][CH2:24][N:23]1[C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:10]3[C:3]4[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=4[N:8]([C@@H:33]4[CH2:37][CH2:36][NH:35][CH2:34]4)[C:9]=3[CH3:32])=[CH:12][CH:13]=2)=[CH:20][N:21]=[N:22]1)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1c(-c2ccc(OCc3cnnn3COC(=O)C(C)(C)C)cc2)c2c(N)ncnc2n1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccc(OCc3cnnn3COC(=O)C(C)(C)C)cc2)c2c(N)ncnc2n1[C@@H]1CCNC1
Yield: 77.4 %

Procedure:
(R)-(5-((4-(4-Amino-6-methyl-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (84) (121 mg, quant. yield) was prepared by treating (R)-tert-butyl 3-(4-amino-6-methyl-5-(4-((1-(pivaloyloxymethyl)-1H-1,2,3-triazol-5-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (83) (188 mg, 0.31 mmol) with TFA in a similar manner as described in Example 1. LC-MS (ESI): m/z (M+1) 505.0.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21]([OH:40])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[C:1]([OH:20])(=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:21][CH3:22].[C:21]([OH:40])(=[O:39])[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]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCC=CC=CC(=O)O

Procedure:
A number of enzymes are involved in PUFA biosynthesis including elongases (ELO) (FIG. 1). For example, linoleic acid (LA, 18:2n-6) is produced from oleic acid (OA, 18:1n-9) by a Δ12-desaturase. Eicosadienoic acid (EDA, 20:2n-6) is produced from linoleic acid (LA, 18:2n-6) by a Δ9-elongase. Dihomo-γ-linolenic acid (DGLA, 20:3n-6) is produced from eicosadienoic acid (EDA, 20:2n-6) by a Δ8-desaturase. Arachidonic acid (AA, 20:4n-6) is produced from dihomo-γ-linolenic acid (DGLA, 20:3n-6) by a Δ5-desaturase.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][C:14]([Si:17]([CH3:30])([CH3:29])[O:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:16])[CH3:15].[OH-].[Na+]>C(Cl)Cl>[CH3:16][C:14]([Si:17]([CH3:30])([CH3:29])[O:18][CH2:19][CH2:20][N:21]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[S:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])(=[O:11])=[O:10])([CH3:13])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCCNCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)S(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.7 %

Procedure:
The following process was carried out according to literature precedent (JOC, 1988, 53 (7), 1372). 2,4-Difluorobenzenesulphonyl chloride (436 mg, 2.05 mmol) was added slowly to a stirred solution of 2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-N-(phenylmethyl)ethanamine (600 mg, 2.26 mmol) in a 1:1 mixture of 10% sodium hydroxide solution and DCM (80 mL) at 0° C. The reaction mixture was allowed to warm up to RT and left to stir for 5 hours. The phases were separated and the aqueous phase was extracted with DCM (3×50 mL). The combined extracts were dried (MgSO4), filtered and evaporated to afford the title compound as a colourless oil (939 mg).