Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[NH:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)([CH3:3])[CH3:2].[C:36]1(S(NC2C=CC(C(F)(F)F)=CC=2NCC2C=CC(C(OC)=O)=CC=2)(=O)=O)C=CC=CC=1.[H-].[Na+].CI>CN(C=O)C>[CH3:36][N:15]([CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)[C:6]1[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]=1[N:4]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:1]([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(CNc2cc(C(F)(F)F)ccc2N(C(C)C)S(=O)(=O)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(CNc2cc(C(F)(F)F)ccc2NS(=O)(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(C)c2cc(C(F)(F)F)ccc2N(C(C)C)S(=O)(=O)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 4-[2-(N-Isopropyl-phenylsulfonylamino)-5-trifluoromethylphenylaminomethyl]benzoate (200 mg) prepared by the same procedure as Example 17 by using methyl 4-(2-phenylsulfonylamino-5-trifluoromethylphenylaminomethyl)benzoate (prepared in Example 27.) was dissolved in DMF (5 ml). Sodium hydride (64 mg) and methyl iodide (200 μl) were added thereto. The mixture was stirred for 24 hours at 60° C. The reaction mixture was extracted with H2O-AcOEt, washed, dried over, filtered and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=5:1) to give the title compound (105 mg) having the following physical data.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[CH2:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:19][CH2:20][C:21]#[CH:22]>CCCCCCC.CCOC(C)=O>[C:23]1([CH2:18][CH2:19][CH2:20][C:21]#[C:22][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C#CCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccnc2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C(#Cc1cccnc1)CCCc1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid pyridin-3-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (80 mg, 72%); 1H NMR δ (CDCl3): 8.62-8.63 (m, 1H), 8.48-8.46 (m, 1H), 7.68-7.64 (m, 1H), 7.21-7.17 (m, 6H), 2.76 (t, J=7.11 Hz, 2H), 2.4 (t, J=7.10 Hz, 2H), 1.91 (p, J=7.12 Hz, 2H); LCMS m/z: 221.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](NC(=O)OCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2S,4S)-4-Aminopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (7.3 g, 30 mmol) was dissolved in DCM (100 mL) and cooled in an ice bath. DIPEA (3 equiv) was added, followed by benzyl chloroformate (1 equiv). The mixture was stirred at room temperature for 3 hours and then diluted with DCM (200 mL). The solution was washed with 1M HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL), then dried over Na2SO4. The solvent was evaporated to afford the title compound (10.4 g, 28 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C12H21NO7S, 323.4. found 324.3.
Reaction SMILES: O.[OH-].[Li+].CC([Si](C)(C)[O:9][C:10]1[CH:11]=[C:12]([CH:23]=[C:24]([O:26][C@@H:27]([CH3:37])[CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:25]=1)[C:13]([NH:15][C:16]1[CH:21]=[N:20][C:19]([CH3:22])=[CH:18][N:17]=1)=[O:14])(C)C>O.C1COCC1>[CH3:34][C:33]([Si:30]([CH3:31])([CH3:32])[O:29][CH2:28][C@@H:27]([O:26][C:24]1[CH:23]=[C:12]([CH:11]=[C:10]([OH:9])[CH:25]=1)[C:13]([NH:15][C:16]1[CH:21]=[N:20][C:19]([CH3:22])=[CH:18][N:17]=1)=[O:14])[CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1cnc(NC(=O)c2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 0.1 %

Procedure:
Lithium hydroxide monohydrate (0.38 g, 9.12 mol) in water (20 mL) was added to a solution of 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide (1.94 g, 3.65 mol) in THF (40 mL) and stirred at RT for 20 hours. The THF was removed in vacuo and the aqueous layer was adjusted to pH7. Ethyl acetate (50 mL) and water (50 mL) were added then the aqueous layer re-extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The crude material was chromatographed on silica, eluting with 20-50% ethyl acetate in isohexane, to give the desired material as a white solid (0.8 g). 1H NMR δ (CDCl3): 0.04 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H), 1.30 (d, 3H), 2.56 (s, 3H), 3.65-3.81 (m, 2H), 4.46-4.51 (m, 1H), 5.63 (s, 1H), 6.63 (t, 1H), 6.98 (t, 1H), 7.04 (t, 1H), 8.15 (s, 1H), 8.41 (s, 1H), 9.57 (s, 1H); m/z 418 (M+H)+
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[C:1]1([C:7]#[C:8]/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: CCCCCC/C=C/I
Product: CCCCCC/C=C/C#Cc1ccccc1

Procedure:
The general procedure was used to convert phenylacetylene and (E)-1-iodooctene to the title product in 24 hours. Purification by flash chromatography (light petroleum ether as eluent) gave the analytically pure product as a clear oil (423 mg, 99% yield). 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 2H), 7.28 (m, 3H), 6.24 (m, 1H), 5.68 (d, J=15.84, 1H), 2.15 (q, 2H), 1.41-1.28 (m, 8H), 0.89 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 145.08, 131.24, 128.07, 127.67, 123.49, 109.32, 88.23, 87.68, 33.08, 31.52, 28.66, 28.59, 22.45, 13.94. Anal. Calc'd. for C16H20: C, 90.51; H, 9.49; Found C, 90.65; H, 9.58.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24]([O:27][CH2:28][CH2:29]Br)(=[O:26])[CH3:25]>CN(C=O)C.O>[C:7]1([C:13]([CH2:29][CH2:28][O:27][C:24](=[O:26])[CH3:25])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)OCCBr
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCOC(C)=O)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
A solution of potassium tert.butoxide (448 g, 4M) in DMF (2 l) under nitrogen at room temperature was treated dropwise with diethyl phenylmalonate (945 g, 4M). 1-Acetoxy-2-bromoethane (668 g, 4M) was added. The reaction was allowed to cool to room temperature after 45 mins and was diluted with water (5 l) then extracted with IPE (2 l, 500 ml). The extracts were washed, dried and evaporated to give the title compound (1300 g). Bp 130°/0.05 mm.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=1)([O-])=O.[CH2:16]([N:18](CC)[CH2:19][CH3:20])[CH3:17].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl.CCOCC>[CH2:16]([N:18]([CH2:19][CH3:20])[C:9]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:8]=1)[CH3:17]
Reactant: O=[N+]([O-])c1ccnc(N2CCNCC2)c1
Reactant: CCN(CC)CC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CCN(CC)c1ccc(N2CCNCC2)nc1
Reaction time: 1 h

Procedure:
The amine (21 g), triethylamine (17.9 g) and methylene chloride (600 ml) are cooled to 0°. Di-t-butyl dicarbonate (25.8 g) in methylene chloride (200 ml) is added over 30 min at 0°. The reaction mixture is stirred at 0° for 1 hr and allowed to warm to 20-25°. The reaction mixture is washed with saturated sodium bicarbonate (3×200 ml), dried over potassium carbonate and the solvent removed under reduced pressure to give a solid. The solid is dissolved in ether, petroleum ether is added until the mixture is cloudy, the mixture is filtered thru celite and the filtrate is concentrated to give the protected piperazine compound.
Reaction SMILES: [CH2:1](C([Sn])=C(CCCC)CCCC)[CH2:2]CC.Br[C:17]1[CH:22]=[C:21]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1[NH:36][C:37](=[O:45])[C@:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40]>C1(C)C=CC=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].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:1]([C:17]1[CH:22]=[C:21]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1[NH:36][C:37](=[O:45])[C@:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])=[CH2:2]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cc1Br)C(F)(F)F
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(S(=O)(=O)c2ccc(S(C)(=O)=O)cc2)ccc1NC(=O)[C@@](C)(O)C(F)(F)F
Reaction time: 7 h

Procedure:
Tributylvinyltin (0.28 ml) was added to a deoxygenated suspension of (R)-N-[2-bromo-4-(4-mesylphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 140) (0.50 g) and tris(dibenzylideneacetone)dipalladium(O) (0.05 g) in anhydrous toluene (10 ml). The mixture was heated under reflux with stirring. After 14 hours a further portion of tris(dibenzylideneacetone)dipalladium(0) (0.05 g) and tributylvinyltin (0.28 ml) was added and heating was continued for a further 7 hours. The reaction mixture was allowed to cool and volatile materials were removed by evaporation. The residue was purified on a silica gel Mega Bond Elut column eluting with 5-50% ethyl acetate/hexane to give the title compound (0.146 g) as a solid. NMR (CDCl3) 1.74 (s, 3H), 3.06 (s, 3H), 5.65-5.82 (dd, 2H), 6.67-6.77 (dd, 1H), 7.86-7.89 (dd, 1H), 7.95 (s, 1H), 8.06-8.16 (m, 4H), 8.35 (d, 1H), 8.79 (s, 1H); MS (ESP−): 477.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[C:24](=[O:27])([O-])[O-].[Cs+].[Cs+]>C1(CO)CCCCC1>[CH:11]1([CH2:24][O:27][C:16]2[S:17][C:13]3[CH:12]=[C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:23])[CH:9]=4)[CH:22]=[CH:21][C:14]=3[N:15]=2)[CH2:22][CH2:21][CH2:14][CH2:13][CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Agent: OCC1CCCCC1
Agent: [Cs+]
Product: CNC(=O)c1cc(Oc2ccc3nc(OCC4CCCCC4)sc3c2)ccn1
Temperature: 90 °C
Reaction time: 12 h
Yield: 81.9 %

Procedure:
N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (15 mg, 43 μmol) was mixed with 500 μL of cyclohexylmethanol and cesium carbonate (42 mg, 0.13 mmol). The resulting reaction mixture was stirred at 90° C. for 12 hours. The crude reaction mixture was filtered and purified on prep HPLC and then evaporated in vaccuo to give 4-(2-(cyclohexylmethoxy)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (7 mg, 17.6 μmol) as powder. ES/MS m/z 398.1 (MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:16][C:15]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(I)c4)[nH]c3c2)CC1
Reactant: C#Cc1ccc(NC2CC2)nn1
Product: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(C#Cc5ccc(NC6CC6)nn5)c4)[nH]c3c2)CC1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole in a manner similar to that described for in Example 1. The title compound was obtained as a khaki solid. Mp: 130-131° C.; 1H NMR (300 MHz, CDCl3) δ: 8.11-8.13 (1H, d, J=6.0 Hz), 7.86 (1H, s), 7.64 (2H, m), 7.42-7.45 (1H, d, J=9.0 Hz), 7.39-7.42 (1H, d, J=9.0 Hz), 7.22 (1H, s), 7.01-7.04 (1H, d, J=9.0 Hz), 6.00 (1H, s), 3.61 (2H, s), 2.60 (1H, m), 2.44 (8H, brs), 2.27 (3H, s), 0.87-0.89 (2H, m), 0.65 (2H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C28H29ClN7: 498.2167. found: 498.2150.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=4[N:17]=3)=[CH:12][CH:11]=2)=[CH2:9])=[CH:4][CH:3]=1.N#N>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=4[N:17]=3)=[CH:14][CH:15]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C=C(c1ccc(Cl)cc1)c1ccc(-c2nc3cc(C(N)=O)ccc3[nH]2)cc1
Agent: N#N
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(c1ccc(Cl)cc1)c1ccc(-c2nc3cc(C(N)=O)ccc3[nH]2)cc1
Yield: 69.8 %

Procedure:
A flask containing a solution of 2-{4-[1-(4-chloro-phenyl)-vinyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide (Example 41, 30 mg, 0.08 mmol) in 1:1 ethanol/ethyl acetate (6.0 mL) was charged with N2 and evacuated (3×). Palladium on carbon (10 wt %) was added to the solution, and the flask was charged with H2 and evacuated (3×), and then maintained at ˜1 atm H2 for 2.5 h. The flask was evacuated and then charged with N2. The reaction mixture was filtered through a pad of Celite®, which was washed with ethanol (50 mL), ethyl acetate (50 mL) and then methanol (2×50 mL). The filtrate was concentrated under reduced pressure. Purification of the residue by chromatography (silica gel, 1% methanol saturated with ammonia/9% methanol/CH2Cl2) afforded the title compound (21 mg, 68%). TLC (silica, 1% methanol, saturated with ammonia/9% methanol/CH2Cl2): Rf=0.35. MS (ESI+): mass calculated for C22H18ClN3O, 375.1, m/z found, 376.1 [M+H]+. 1H NMR (500 MHz, CD3OD): δ 8.16 (br s, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.62 (br s, 1H), 7.43 (d, J=8.3 Hz, 2H), 7.30–7.26 (m, 4H), 4.27–4.24 (m, 1H), 1.67 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:22]([CH3:29])[CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:10]=2[CH:9]=1)=S)[CH2:2][CH2:3][CH3:4].C(O)(=[O:32])C>C(OCC)C>[CH2:1]([NH:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:22]([CH3:29])[CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:10]=2[CH:9]=1)=[O:32])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reactant: CC(=O)O
Solvent: CCOCC
Product: CCCCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 20 °C
Reaction time: 5 h

Procedure:
A suspension of N-butyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (1.2 g) and mercuric acetate (1 g) in acetic acid (15 cc) is stirred for 5 hours at a temperature in the region of 20° C. The black suspension obtained is diluted with ethyl ether (25 cc) and filtered. The solid is washed with ethyl ether (2×10 cc). The combined organic phases are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is taken up with ethyl acetate (25 cc) and distilled water (25 cc). The organic phase is separated, filtered, dried over magnesium sulphate, filtered again and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The very viscous residual oil (1.1 g) is taken up with a mixture (83:17 by volume) (12 cc) of ethyl acetate and methanol warmed to about 50° C. After 1 hour at a temperature in the region of 20° C., the solid formed is drained, washed with diethyl ether (2×10 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. N-butyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]- 2-phenothiazinecarboxamide (0.4 g) is thereby obtained in the form o cream-coloured crystals, m.p. 218° C.
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(O)(=O)CCCC/C=C\C/C=C\C/C=C\CCCCC.CC/C=C\C/C=C\C/C=C\CCCCCCCC(O)=O>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(=O)O

Procedure:
FIG. 23 shows the results of the feeding experiments with the yeast cells which comprise plasmid pYES52Dest-MaLPAAT (MaB4_AT). In FIG. 23, A/B, the yeast cultures were fed linoleic acid (18:2 Δ9,12). In comparison with the control culture (FIG. 23, A), the yeast cells with the MaLPAAT showed a markedly higher conversion (increased 4-fold) of 18:2 into γ-linolenic acid (18:3 Δ6,9,12), and a 3.5-fold increase of the fatty acid 20:2 Δ11,14 elongated from 18:2. Analogously, when feeding linolenic acid (18:3 Δ9,12,15), a markedly higher conversion rate to give stearidonic acid (18:4 Δ6,9,12,15) and isoarachidonic acid (20:4 Δ8,11,14,17) was observed in comparison with the controls (FIG. 24).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[O:29]=[C:30]1[NH:34][CH:33]([C:35](O)=[O:36])[CH2:32][CH2:31]1>C1COCC1.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][C:35]([CH:33]4[CH2:32][CH2:31][C:30](=[O:29])[NH:34]4)=[O:36])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: O=C1CCC(C(=O)O)N1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNC(=O)C1CCC(=O)N1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 10 %

Procedure:
A round bottom flask was charged with (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.08 g, 0.2 mmol), 5-oxopyrrolidine-2-carboxylic acid loaded TFP resin (1.4 mmol/g loading, 0.2 mmol), and a THF-DCM solution (3 ml) at 0° C. The resulting solution was shaken vigorously at 0° C. for 45 min and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.013 g, 10%). 1H NMR (400 MHz, CD3OD) δ 7.41-7.32 (m, 2H), 7.21-7.13 (m, 1H), 7.05-6.97 (m, 2H), 6.05 (s, 1H), 5.21-5.02 (m, 1H), 4.34-4.19 (m, 3H), 2.44-2.28 (m, 3H), 2.11-1.98 (m, 1H), 1.88-1.81 (m, 1H), 1.51 (d, J=5.2 Hz, 3H), 0.99-0.86 (m, 2H), 0.69-0.61 (m, 2H). MS: Calcd.: 495. Found: [M+H]+ 496.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[CH2:27]([O:31][C:32]([NH:34][C@H:35]([CH2:40]O)[C:36]([F:39])([CH3:38])[CH3:37])=[O:33])[CH2:28][CH2:29][CH3:30]>ClCCl>[CH2:27]([O:31][C:32]([NH:34][CH:35]([C:36]([F:39])([CH3:38])[CH3:37])[CH2:40][I:20])=[O:33])[CH2:28][CH2:29][CH3:30]
Reactant: II
Reactant: CCCCOC(=O)N[C@H](CO)C(C)(C)F
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCOC(=O)NC(CI)C(C)(C)F
Yield: 78.6 %

Procedure:
To a well-stirred mixture of polystyryl supported triphenylphosphine (29.3 mmol) in dry dichloromethane (40 mL) under a nitrogen atmosphere was added iodine (7.44 g, 29.3 mmol). After ten minutes, imidazole (2.0 g, 29.3 mmol) was added, followed in ten minutes by a solution of N-butoxycarbonyl-3-fluorovalinol (13.3 mmol) in dichloromethane (200 mL). The mixture was heated to reflux for two hours. The cooled mixture was filtered through celite and the filtrate was evaporated. The residue was dissolved in diethyl ether (150 mL), and this solution was washed with dilute aqueous sodium thiosulfate (1×75 mL) and water (2×75 mL). The organic layer was dried (Na2SO4), filtered through a pad of silica gel and evaporated to afford 3.46 g of N-butoxycarbonyl-1-iodo-2-amino-3-fluoro-3-methyl-n-butane: 1H NMR (CDCl3) δ4.72 (br d, 1H), 3.86 (br m, 1H), 3.56 (dd, 1H), 1.47 (s, 9H), 1.43 (m, 6H) ppm.
Reaction SMILES: C(OC([N:11]1[CH:16]2[CH2:17][CH2:18][CH2:19][CH:12]1[C:13](=[O:30])[N:14]([CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:15]2)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:23]([O:22][CH2:21][CH2:20][N:14]1[CH2:15][CH:16]2[NH:11][CH:12]([CH2:19][CH2:18][CH2:17]2)[C:13]1=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1C2CCCC(CN1CCOCc1ccccc1)N2C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1C2CCCC(CN1CCOCc1ccccc1)N2
Yield: 91.1 %

Procedure:
3-(2-Benzyloxyethyl)-2-oxo-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound 5, 0.15 g, 0.36 mmol) was dissolved in MeOH (5 mL), and palladium (10%) on activated carbon (0.03 g) was added. Hydrogen was applied via balloon for 1 hour. The black suspension was then filtered through compacted Celite, and the methanol was removed by high-vacuum rotary evaporator to give Compound 6 (0.09 g, 90%) as a thick oil, which was of sufficiently good quality to be advanced to the coupling reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[S:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[C:13]([C:18]#[N:19])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1.[I:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[OH:39].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:39][C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[I:31])=[C:13]([C:18]#[N:19])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1
Reactant: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: Oc1ccc(F)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2ccc(Oc3ccc(F)cc3I)c(C#N)c2)c(OC)c1

Procedure:
N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-N-(2,4-dimethoxybenzyl)-4-fluorobenzenesulfonamide (Preparation 207, 410 mg, 0.876 mmol), 2-iodo-4-fluorophenol (Preparation 218, 229 mg, 0.964 mmol) and potassium carbonate (363 mg, 2.63 mmol) in dimethyl sulphoxide (20 ml) were stirred at room temperature under nitrogen for 18 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (3×30 ml). The combined organics were washed with saturated aqueous sodium chloride solution (30 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as an off-white solid, 670 mg, quantitative yield.