Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:10][C:9](=[S:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21][CH2:22]CCCC.C(I)C>CN(C)P(=O)(N(C)C)N(C)C>[CH2:21]([S:18][C:9]1[S:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH3:22]
Reactant: CCCCCC
Reactant: S=C1N=C(c2ccccc2)C(c2ccccc2)S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCI
Product: CCSc1nc(-c2ccccc2)c(-c2ccccc2)s1
Temperature: 0 °C

Procedure:
5 g of 4,5-bis-phenylthiazoline-2-thione are dissolved in 50 ml of hexamethylphosphoric acid triamide, the solution is cooled to 5° and, while stirring, sodium hydride (0.89 g of a 50% strength suspension in mineral oil, de-oiled with hexane) is added. The mixture is stirred for 30 minutes at room temperature, then 3.18 g of ethyl iodide are slowly added dropwise and the mixture is then stirred for 30 minutes at room temperature, poured onto 1000 ml of ice-water and extracted by shaking twice with diethyl ether. The ether phases are combined, washed with water, dried over magnesium sulphate and concentrated to dryness by evaporation. The remaining pale yellow oil is dissolved in 200 ml of toluene/hexane (1:1) and filtered through 10 g of silica gel. Concentration of the eluate by evaporation yields 2-ethylthio-4,5-bis-phenylthiazole in the form of an oil.
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>>[CH3:18][CH2:17]/[CH:16]=[CH:15]\[CH2:14]/[CH:13]=[CH:12]\[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19]
Reactant: CCCCC/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\CCCCCCCC(=O)O

Procedure:
The increase in the conversion rate of PUFAs, which had been observed for the total extracts, was clearly also monitored in the neutral lipids. As regards the feeding of linoleic acid (FIGS. 25 A and B), a 2-fold increase in the conversion of linoleic acid into γ-linolenic acid (18:3 Δ6,9,12) and a 3-fold increase in the 20:2 Δ9,12 content was observed. The feeding of linolenic acid (FIG. 26, C and D) gave similar data (conversion of 18:3 into 18:4 3-fold, of 18:3 into 20:3 3-fold).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2C[CH:25]([C:27]([OH:29])=[O:28])[CH2:24]2)[CH:16]=[C:15]3[CH:30]2[CH2:32][CH2:31]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([C@H]1CC[C@H](OC2C=C3C(=CC=2)N=C(CNCCC(O)=O)C=C3C)CC1)(C)(C)C>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][NH:23][CH2:24][CH2:25][C:27]([OH:29])=[O:28])[CH:16]=[C:15]3[CH:30]2[CH2:31][CH2:32]2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CC(C(=O)O)C4)cc(C4CC4)c3c2)CC1
Agent: Cc1cc(CNCCC(=O)O)nc2ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)cc12
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CNCCC(=O)O)cc(C4CC4)c3c2)CC1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-cyclopropyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid using the appropriate intermediate available from the synthesis of 3-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-methyl-quinolin-2-ylmethyl]-amino}-propionic acid.) ESI-MS (M+H+): 425.3; 1H NMR (400 MHz, METHANOL-d4) Shift 8.00 (d, J=9.29 Hz, 1H), 7.72 (d, J=2.51 Hz, 1H), 7.43 (dd, J=2.64, 9.16 Hz, 1H), 7.14 (s, 1H), 4.50 (s, 2H), 4.40-4.49 (m, 1H), 3.44 (t, J=6.78 Hz, 2H), 2.87 (t, J=6.65 Hz, 2H), 2.44-2.54 (m, 1H), 2.32 (d, J=11.04 Hz, 2H), 1.91-1.99 (m, 2H), 1.42-1.54 (m, 2H), 1.21-1.36 (m, 4H), 1.07-1.21 (m, 1H), 0.94 (s, 9H), 0.84-0.92 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH3:9])[CH:3]([OH:6])[C:4]#[CH:5].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:18]([Si:15]([CH3:17])([CH3:16])[O:6][CH:3]([CH:2]([CH3:1])[CH2:7][CH2:8][CH3:9])[C:4]#[CH:5])([CH3:21])([CH3:20])[CH3:19]
Reactant: C#CC(O)C(C)CCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CC(O[Si](C)(C)C(C)(C)C)C(C)CCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a solution of 4-methyl-hept-1-yn-3-ol (2.53 g, 0.02 mol) in dry DMF (25 mL) were added imidazole (1.63 g, 0.024 mol) and tert-butyldimethylsilyl chloride (3.62 g, 0.024 mol). The resulting solution was stirred at RT for 18 h and then treated with saturated NH4Cl (15 mL) and EtOAc (120 mL). The organic layer was washed with saturated NH4Cl (20 mL), water (4×20 mL), brine (2×20 mL), dried over sodium sulfate, and concentrated in vacuo to afford a crude product (4.65 g, 97%), as a yellow oil, which was used in the next step without further purification. Rf 0.9 (EtOAc/hexanes 1/9); 1H NMR (CDCl3) δ 0.08 (s, 3H), 0.12 (s, 3H), 0.96-0.85 (m, 15H), 1.57-1.10 (m, 4H), 1.69-1.61 (m, 1H), 2.33 (t, J=2.20 Hz, 1H), 4.22-4.18 (m, 1H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[BH4-]>CC(O)C>[CH2:3]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccccc1C=NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Oc1ccccc1CNCc1ccccc1
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Sodium borohydride (0.2 g) was added in small portions to 3 mL of dry 2-propanol in a nitrogen atmosphere. To this mixture was added dropwise a solution of 1.0 g of 2-(benzylimino-methyl)-phenol in 3 mL of 2-propanol. After complete addition, stirring was continued for 1 h. Then water was added in order to decompose excess borohydride, and the volatiles were removed in vacuo. The residue was redissolved in ethyl acetate, washed with water, dried (sodium sulfate) and concentrated yielding 0.9 g of 2-(benzylamino-methyl)-phenol as an oil. EI-MS: 213 (M+).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[CH3:19].[OH-].[K+]>C(Cl)Cl>[N+:15]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=1[O:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:18][CH3:19])=[CH:22][CH:23]=1)[C:6]([O:8][CH3:9])=[O:7])([O-:17])=[O:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CCOc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)OC)cc2[N+](=O)[O-])cc1
Temperature: 150 °C
Yield: 74 %

Procedure:
A mixture of 13 g (50 mmole) of methyl 4-chloro-3,5-dinitrobenzoate, 7.45 g (54 mmole) of 4-ethoxyphenol, and 13 ml of potassium hydroxide solution (3.03 g, 54 mmole) was heated under argon at 150° C. for 4 h. The mixture was cooled and partitioned between 130 ml of 2 N sodium hydroxide solution and 400 ml of dichloromethane. The organic layer was washed with 2×100 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated under high vacuum to give 14.5 g, which was chromatographed on a silica gel column (5 cm×50 cm), eluting with 25% hexane/75% dichloromethane to give 13.2 g (74% yield). TLC (silica gel, CH2Cl2), Rf0.80. NMR: 1H (300 MHz) (CDCl3) 1.39 (3H, t, —CH3); 3.97 (2H, q, —CH2—); 4.02 (3H, s, —OCH3); 6.81 (4H, s, arom); and 8.70 ppm (2H, s, arom).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[CH2:16](O)[CH2:17][OH:18].O>C1(C)C=CC=CC=1>[C:10]1([C:5]2([C:8]#[N:9])[CH2:4][CH2:3][C:2]3([O:18][CH2:17][CH2:16][O:1]3)[CH2:7][CH2:6]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCCO
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2ccccc2)CCC2(CC1)OCCO2
Reaction time: 3 h

Procedure:
The title compound of step 2 (43.3 g, 217 mmol) and ethylene glycol (27.4 g, 435 mmol) were boiled in toluol (430 mL) with the addition of p-toluol sulphonic acid (1.87 g, 10.9 mmol) at a water separator for 3 h with reflux. After the reaction had ended, the mixture was cooled, washed with NaHCO3 solution and saturated NaCl solution, dried with Na2SO4 and concentrated to low volume in a vacuum.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[C:5](O)=[O:6].C(Cl)[Cl:17].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[Br:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[C:5]([Cl:17])=[O:6]
Reactant: ClCCl
Reactant: O=C(O)C(CCBr)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)C(CCBr)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
Dissolve the product of Step 2 (8.1 g, 25.96 mmoles) in 20 ml. of dry CH2Cl2. Add oxalyl chloride (8.1 g, 62.3 mmoles), followed by 50 μl of dry DMF and heat the solution to reflux for 3 h. Cool the solution to room temperature and remove the solvent and excess reagent using reduced pressure. Yield: 8.2 g (IR: 1785 cm-1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][C:27]#[N:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:24][CH2:25][CH2:26][C:27]#[N:28])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
A mixture of [4-(4-hydroxyphenyl)butyl]carbamic acid benzyl ester 1 (2.00 g, 6.70 mmol), 4-bromobutyronitrile (0.70 mL, 6.70 mmol), and potassium carbonate (1.00 g, 7.4 mmol) in DMF (10 mL), was stirred at 65° C. for 16 h. Solvent was removed by rotary evaporation and the residue was taken up in ethyl acetate, washed with water and brine, and concentrated under vacuum. The crude product was purified by flash silica gel column chromatography eluting with ethyl acetate/CH2Cl2 (1:9, v/v) to give the desired product 2 as a white solid (1.80 g, 75% yield). 1H NMR (300 MHz, CDCl3) δ 1.56 (m, 4H), 2.15 (m, 2H), 2.55 (m, 4H), 3.15 (m, 2H), 4.00 (m, 2H), 4.70 (br s, 1H), 5.10 (s, 2H), 6.80 (d, 2H), 7.05 (d, 2H), 7.30 (m, 5H). m/z (ESI): 367 [C22H26N2O3+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[Cl-].[Cl-].[Cl-].[Al+3].[CH2:16]([C:18]12[CH2:33][CH2:32][C:31](=O)[C:30]([CH3:35])=[C:29]1[C:28]1[CH:27]=[CH:26][C:25]3[NH:24][N:23]=[CH:22][C:21]=3[C:20]=1[CH2:19]2)[CH3:17]>C(OCC)C>[CH2:16]([C:18]12[CH2:33][CH2:32][CH2:31][C:30]([CH3:35])=[C:29]1[C:28]1[CH:27]=[CH:26][C:25]3[NH:24][N:23]=[CH:22][C:21]=3[C:20]=1[CH2:19]2)[CH3:17]
Reactant: CCC12CCC(=O)C(C)=C1c1ccc3[nH]ncc3c1C2
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC12CCCC(C)=C1c1ccc3[nH]ncc3c1C2
Reaction time: 0.38 h

Procedure:
A solution of lithium aluminum hydride in THF (1.0M, 0.26 mL, 0.26 mmol) was diluted with diethyl ether (2 mL) and solid aluminum trichloride (0.098 g, 0.74 mmol) was added in portions. To the resulting solution was added a suspension of 9a-ethyl-6-methyl-8,9,9a,10-tetrahydroindeno[2,1-e]indazol-7(3H)-one (0.027 g, 0.10 mmol) in diethyl ether (1.5 mL). After 23 minutes, the reaction was quenched by the addition of EtOAc (0.5 mL) followed by 2N hydrochloric acid (0.5 mL). The reaction mixture was partitioned between EtOAc and water and the organic phase was washed with brine and dried over MgSO4. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel (elution with 1:3 EtOAc/hexanes) to give 9a-ethyl-6-methyl-3,7,8,9,9a,10-hexahydroindeno[2,1-e]indazole.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([CH3:29])[CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:33][CH2:34]1
Reactant: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f53) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.CC([O-])(C)C.[K+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(NCc2cc(-c3cccc(F)c3)ccc2F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(NCc2cc(-c3cccc(F)c3)ccc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a mixture of 3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenol (300 mg, 0.96 mmol, 1.0 eq.) and t-BuOK (216 mg, 1.90 mmol, 2.0 eq) in DMF (3 mL) was added dropwise ethyl bromoacetate (193 mg, 128 uL, 1.20 mmol, 1.2 eq) at 0° C. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with water and neutralized with 1 M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by chromatography (petroleum ether: EtOAc, 4:1) to give the title compound as a colourless oil (200 mg, 52%).
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C([O:7][CH2:8][C:9]1[C:10]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]([Br:19])[C:11]=2[S:12][CH:13]=1)=O.CO.O>C1COCC1.CCCCCC>[Br:19][C:14]1[C:11]2[S:12][CH:13]=[C:9]([CH2:8][OH:7])[C:10]=2[C:17]([CH3:18])=[CH:16][CH:15]=1
Reactant: Cc1ccc(Br)c2scc(COC(=O)C(F)(F)F)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(Br)c2scc(CO)c12
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a solution of sodium borohydride (2.78 g, 100 mmol) in THF (200 ml), a solution of (7-bromo-4-methylbenzo[b]thiophene-3-yl)methyl trifluoroacetate (74.46 g, 199 mmol) in THF (100 ml) was added at room temperature, and stirred at room temperature. The reaction vessel containing the reaction mixture was placed in an ice bath, to which methanol (30 ml) was slowly added dropwise. It was stirred for 10 minutes as it was in the ice bath, and water (600 ml) was added the reaction mixture. The reaction mixture was transferred to a separatory funnel and 1200 ml of hexane was added thereto. On shaking the separatory funnel, a sludgy black substance formed at the bottom of the aqueous phase, which was removed. After further washing the organic phase with water (300 ml×6 times), the organic phase was dried on magnesium sulfate and the solvent was evaporated to obtain an orange solid 7-bromo-3-hydroxymethyl-4-methyl-benzo[b]thiophene (46.13 g, 179 mmol). The yield was 90%.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([C:33]3([CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)O1>>[C:41]([O:40][C:39](=[O:45])[NH:38][CH2:37][C:33]1([C:30]2[CH:29]=[CH:28][C:27]([C:2]3[C:3]4[C:4]5[CH:18]=[CH:17][S:16][C:5]=5[C:6](=[O:15])[NH:7][C:8]=4[C:9]([CH3:14])=[CH:10][C:11]=3[O:12][CH3:13])=[CH:32][CH:31]=2)[CH2:36][CH2:35][CH2:34]1)([CH3:44])([CH3:42])[CH3:43]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(CNC(=O)OC(C)(C)C)CCC2)cc1
Yield: 45 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.46 mmol) was reacted with tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)methylcarbamate (270 mg, 0.70 mmol to afford the desired product (105 mg, 45%) as a light brown solid: ESI MS m/z 505 [C29H32N2O4S+H]+.
Reaction SMILES: O=O.[C:3]1([CH:9]=[CH:10][CH:11]([OH:13])[CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pt].O>[CH:9](=[CH:10][C:11](=[O:13])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(O)C=Cc1ccccc1
Agent: [Pt]
Agent: O=O
Solvent: O
Product: CC(=O)C=Cc1ccccc1
Yield: 87.5 %

Procedure:
In an ambient pressure oxygen atmosphere, 29.2 mg of 4-phenyl-but-3-ene-2-ol and 33.9 mg of the platinum catalyst obtained in Example 1 were agitated for fifteen hours at 60° C. in 2 ml of water. The reaction mixture was subsequently extracted using ethyl acetate, and the organic layer was dried using magnesium sulfate, filtered and concentrated to obtain 25.2 mg (87% yield) of benzalacetone. The reaction equation and the analytical results of the product are shown below.
Reaction SMILES: [C:1]([C@@:8]([NH2:23])([CH2:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)C(O)=O)([O:3][C:4](C)(C)C)=[O:2]>CO>[CH3:4][O:3][C:1](=[O:2])[C@@H:8]([NH2:23])[CH2:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(CSC[C@@](N)(C(=O)O)C(=O)OC(C)(C)C)cc1
Solvent: CO
Product: COC(=O)[C@@H](N)CSCc1ccc(OC)cc1

Procedure:
(R)-2-BOC-amino-3-(4-methoxy-benzylsulfanyl)-propionic acid prepared in Step B of Preparation 27 and methanol were reacted according to the same procedure as
Reaction SMILES: C[O:2]C1C=C2C(=CC=1)NC(=O)/C/2=C/C1C=C2C(C(/C=C/C3C=CC=C[N+]=3[O-])=NN2)=CC=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])/[C:37]/2=[CH:44]/[C:45]1[CH:53]=[C:52]2[C:48]([C:49](/[CH:54]=[CH:55]/[C:56]3[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=3)=[N:50][NH:51]2)=[CH:47][CH:46]=1>>[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])/[C:37]/2=[CH:44]/[C:45]1[CH:53]=[C:52]2[C:48]([C:49](/[CH:54]=[CH:55]/[C:56]3[CH:61]=[CH:60][N+:59]([O-:2])=[CH:58][CH:57]=3)=[N:50][NH:51]2)=[CH:47][CH:46]=1
Reactant: COc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4cccc[n+]4[O-])n[nH]c3c1)C(=O)N2
Reactant: COc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2
Product: COc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4cc[n+]([O-])cc4)n[nH]c3c1)C(=O)N2

Procedure:
According to the procedure for the synthesis of 2-((E)-2-(6-((E)-(5-methoxy-2-oxoindolin-3-ylidene)methyl)-1H-indazol-3-yl)vinyl)pyridine 1-oxide (Example A88), except substituting (E)-5-methoxy-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methyl-ene)indolin-2-one (8.1 mg, 0.021 mmol), the title compound was prepared as an orange solid (1.3 mg, 15%.). 1H NMR (400 MHz, DMSO-d6) δ 13.55 (br. s, 1H), 10.45 (s, 1H), 8.35 (d, J=8.6 Hz, 1H), 8.20 (d, J=6.8 Hz, 2H), 7.93 (s, 1H), 7.79-7.72 (m, 4H), 7.55 (d, J=14.3 Hz, 1H), 7.54 (d, J=8.9 Hz, 1H), 7.17 (d, J=2.7 Hz, 1H), 6.86 (dd, J=8.5, 2.7 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H), 3.60 (s, 3H); MS ESI 411.2 [M+H]+, calcd for [C24H18N4O3+H]+ 411.14.
Reaction SMILES: [F:1][C:2]([F:30])([C:14]1[N:18]2[CH:19]=[C:20]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[CH:21]=[C:22]([F:23])[C:17]2=[N:16][N:15]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([OH:13])=[CH:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CO.C(Cl)Cl.C1COCC1>[F:30][C:2]([F:1])([C:14]1[N:18]2[CH:19]=[C:20]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[CH:21]=[C:22]([F:23])[C:17]2=[N:16][N:15]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([O:13][CH2:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=[CH:6]2
Reactant: OCCCN1CCOCC1
Reactant: Cn1cc(-c2cc(F)c3nnc(C(F)(F)c4ccc5ncc(O)cc5c4)n3c2)cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cc(-c2cc(F)c3nnc(C(F)(F)c4ccc5ncc(OCCCN6CCOCC6)cc5c4)n3c2)cn1
Temperature: 0 °C
Yield: 33 %

Procedure:
To a flask charged with 6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinolin-3-ol (17.3 mg, 42 μmol), was added triphenylphosphine (55 mg, 211 μmol), THF (1 mL), and 4-(3-hydroxypropyl)-morpholine, 95% (31 μl, 211 μmol). The mixture was placed under N2 and cooled to 0° C. Di-tert-butyl azodicarboxylate (49 mg, 211 μmol) was added as a solid in a single portion and the solution was allowed to warm to rt and was maintained for 48 h. The solution was concentrated for purification by MPLC (Teledine Isco combiFlash Companion). The crude residue was taken up in minimal CH2Cl2 and absorbed onto a 5 g loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (40 g) using 99:1 CH2Cl2: MeOH to 90:10 CH2Cl2: MeOH gradient to afford 6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-(3-morpholinopropoxy)quinoline (7.5 mg, 33% yield) as a colorless solid. LRMS (ESI) m/z calcd for C27H27F3N7O2 (M+H) 538.2, found 538.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](S(C)(=O)=O)[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[CH3:28][S:29]([CH2:32][CH2:33][NH2:34])(=[O:31])=[O:30].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:34][CH2:33][CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: Cc1cc(-c2cnc3c(S(C)(=O)=O)cc(Br)nn23)ccc1C(=O)NC1CC1
Reactant: CS(=O)(=O)CCN
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2cnc3c(NCCS(C)(=O)=O)cc(Br)nn23)ccc1C(=O)NC1CC1
Temperature: 160 °C

Procedure:
To a stirred solution of 1.12 g (2.5 mmol) 4-[6-bromo-8-(methylsulfonyl)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methyl benzamide which was prepared according to intermediate example 516b in 15 mL NMP is added 924 mg (7.5 mmol) 2-(methylsulfonyl)ethanamine and 1.94 g (15 mmol) DIPEA and the mixture is heated at 160° C. for 4 h in a heating block. After working up and without further purification 1.18 g (96%) of the title compound are obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15]O)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C=CC(S([Cl:26])(=O)=O)=CC=1.O>N1C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][Cl:26])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO)no1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(CCl)no1
Reaction time: 10 h
Yield: 22.3 %

Procedure:
18.64 g of [5-(t-butyldimethylsilanyloxymethyl)isoxazol-3-yl]methanol was dissolved in 80 ml of pyridine, and 16.06 g of 4-toluenesulfonyl chloride was then added under ice-cooling. The mixture was stirred for 10 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 4.48 g of 5-(t-butyldimethylsilanyloxymethyl)-3-(chloromethyl)isoxazole.