Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si]([C:8]#[C:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:9]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)#[CH:8]
Reactant: CC[Si](C#Cc1ccc2[nH]ccc2c1)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-((triethylsilyl)ethynyl)-1H-indole (from the previous step) in THF (0.2 M) cooled at 0° C. was treated with a solution (0.5 eq.) of tetrabutylammonium fluoride in a dropwise fashion. The reaction mixture turned black and was continued to stir for 30 minutes before warming up to rt. TLC showed full conversion. The reaction was quenched with water and was extracted with diethylether. Combined organic layers were dried over anhydrous Na2SO4 and concentrated using rotary evaporator with minim heating. Chromatography (silica gel, diethylether) afforded the product 5-ethynyl-1H-indole as colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:25]3[CH:26]=[CH:27][C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Brc1ccc2c(ccn2Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1

Procedure:
-Benzyl-5-[4-(tert-butyl)phenyl]-1H-indole was prepared by coupling 1-benzyl-5-bromo-1H-indole (1.44 g, 5.03 mmol), and 4-(tert-butyl)phenylboronic acid (1.08 g, 6.07 mmol), using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.204 g, 0.250 mmol), and potassium carbonate (1.39 g, 10.1 mmol) in dioxane (50 mL) and water (5 mL) following the procedure described in Step 1 of Example 11. Purification by flash chromatography (Biotage apparatus) using 0-5% chloroform in hexane as an eluant yielded the title compound as an aqua solid (0.741 g, 43%), mp: 136-137° C. 1HNMR (200 MHz, DMSO-d6): δ 7.8 (s, 1H), 7.2-7.6 (m, 12H), 6.55 (d, 1H, J=2.6 Hz), 5.45 (s, 2H), and 1.3 ppm (s, 9H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]2[C:17]3[C:18]4[C:10](=[C:11]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[NH:12][C:13]=4[CH:14]=[CH:15][CH:16]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:25][Si](C)(C)[N-][Si](C)(C)C.[Na+].CI.O>O1CCCC1>[CH3:25][N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[CH:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH2:8][CH2:9][C:10]([C:18]=23)=[C:11]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(-c2[nH]c3cccc4c3c2CCC4N2CCOCC2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cn1c(-c2ccccc2)c2c3c(cccc31)C(N1CCOCC1)CC2
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A portion (55 mg) of the compound obtained in Example 226 was dissolved in anhydrous tetrahydrofuran (2 ml) and to the solution was added sodium hexamethyldisilazide (1.0 M tetrahydrofuran solution; 0.52 ml) under cooling with ice. After stirring for 30 minutes, methyl iodide (32.3 μl) was added to the mixture, followed by stirring for 15 minutes. After adding further sodium hexamethyldisilazide (1.0 M tetrahydrofuran solution; 0.35 ml), the mixture was stirred for 30 minutes. Then, methyl iodide (21.5 μl) was added and the mixture was stirred for additional 15 minutes. Water was added to the reaction mixture, followed by extraction with two portions of ethyl acetate. The organic layers were combined, washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by preparative TLC (ethyl acetate/hexane=1:2) to yield 35 mg (61%) of the titled compound as a pale yellow solid. Specific rotation: [α]D +21° (25° C., c0.75, chloroform)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH:12]1[C:20]1[N:24]([CH3:25])[N:23]=[N:22][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:38]([O:40][C:41](=[O:46])[CH2:42]C([O-])=O)[CH3:39].[K+].[Cl-].[Mg+2].[Cl-]>C1COCC1>[CH2:38]([O:40][C:41](=[O:46])[CH2:42][C:17]([C@H:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C@@H:12]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[CH2:13]1)=[O:19])[CH3:39]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Cn1nnnc1C1CC(C(=O)O)CCN1C(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OCc2ccccc2)[C@@H](c2nnnn2C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
1-(Benzyloxycarbonyl)-2-(1-methyl-1H-tetrazol-5-yl)piperidine-4-carboxylic acid (0.495 g, 1.43 mmol) (reference compound 37) was dissolved in THF (4 mL) and then di(1H-imidazol-1-yl)methanone (0.349 g, 2.15 mmol) was added. The reaction was stirred overnight at room temperature (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (0.488 g, 2.87 mmol) and anhydrous magnesium chloride (0.273 g, 2.87 mmol) were suspended in THF (4.00 mL) and stirred at 50° C. under nitrogen overnight and then allowed to cool to room temperature (flask 2). The contents of flask 1 was added to flask 2 and stirred under nitrogen over the weekend (72 h). The reaction was quenched by addition of 2 M HCl. The mixture was extracted three times with EtOAc, the combined organic phase was evaporated and purified on a 50 g Biotage column with heptane/EtOAc 88/12-100/0 over 12 CV. Cis-benzyl 4-(3-ethoxy-3-oxopropanoyl)-2-(1-methyl-1H-tetrazol-5-yl)piperidine-1-carboxylate (482 mg, 81%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.25 (t, 3H), 1.89-1.97 (m, 1H), 2.05-2.12 (m, 1H), 2.28-2.34 (m, 1H), 2.59-2.66 (m, 1H), 2.93 (p, 1H), 3.35-3.41 (m, 1H), 3.62 (dd, 2H), 3.85-3.98 (m, 4H), 4.16 (q, 2H), 5.09 (q, 2H), 5.36-5.42 (m, 1H), 7.21-7.37 (m, 5H). MS m/z 416 (M+H)+
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:12][CH:13]=[O:14])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:12][CH2:13][OH:14])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=CCC(Cn1ccnc1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CCO
Solvent: O
Product: OCCC(Cn1ccnc1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 85.5 %

Procedure:
Sodium borohydride (0.52 g) was added in three portions, over 5 minutes, to an ice-cooled solution of 3-(3,4-dichlorophenyl)-4-(imidazol-1-yl)butan-1-al (3.3 g) (see Preparation 18) in ethanol (25 ml). The mixture was stirred for a erther hour before removing the solvent under reduced pressure to give a residue. The residue was then suspended in water (50 ml), cooled to 0° C. and the mixture first acidified to pH1 with 2N aqueous hydrochloric acid solution and then basified to pH14 by addition of solid sodium carbonate before being extracted with ethyl acetate (3×200 ml). The organic phases were combined, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to yield 3-(3,4-dichlorophenyl)-4-(imidazol-1-yl)butan-1-ol (2.84 g) as a cream solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>O1CCCC1>[CH3:15][CH:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:17]([O:19][C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)=[O:18])=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 60 °C
Yield: 71.7 %

Procedure:
5.0 g (24.6 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are dissolved in 150 ml of absolute tetrahydrofuran by heating to 60° C., with stirring. The solution is allowed to cool to room temperature, 5.0 g (24.8 millimoles) of p-nitrophenyl chloroformate are added and the mixture is stirred first for 20 hours at room temperature and then for 5 hours under reflux. It is then concentrated to about 70 ml, 100 ml of water are added and the product is filtered off and recrystallized from dimethylformamide/water at room temperature, giving 6.5 g (72% of theory) of 4,5-dihydro-5-methyl-6-[p-(p-nitrophenoxycarbonylamino)-phenyl]-3(2H)-pyridazinone as yellow crystals, of melting point 177°-178° C.
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[N:4]=[CH:3][CH:2]=1)[N:15]=[C:14]1[C:9]([C:10]([C:19](O)=[O:20])=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:19]([C:10]1[C:9]2[C:14](=[N:15][C:16]3[C:7]([N:8]=2)=[C:6]2[CH:1]=[CH:2][CH:3]=[N:4][C:5]2=[CH:18][CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:20]
Reactant: O=C(O)c1cccc2nc3ccc4ncccc4c3nc12
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4ncccc4c3nc12

Procedure:
Pyrido[3,2-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from pyrido[3,2-α]phenazine-11-carboxylic acid (II.5) and N,N-dimethylethylenediamine
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([C:21]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[C:12]1[C:17]([O:18][CH3:19])=[N:16][C:15]([CH3:20])=[CH:14][N:13]=1)(=[O:10])=[O:9].[Si]([O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[OH:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[C:3]([S:8]([N:11]([C:21]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[C:12]3[C:17]([O:18][CH3:19])=[N:16][C:15]([CH3:20])=[CH:14][N:13]=3)(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:38][CH:37]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1I
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(O)cc1
Yield: 45.5 %

Procedure:
A mixture of 2-iodo- N-(isobutoxycarbonyl)- N-(3-methoxy-5-methylpyrazin-2-yl) benzenesulphonamide (2.0 g), 4-(t-butyldimethylsilyloxy)benzeneboronic acid (1.0 g), prepared by the method described in GB 2276162, tetrakis(triphenylphosphine)palladium(O) (0.25 g), sodium carbonate (0.5 g), dimethoxyethane (10 ml) and water (10 ml) was stirred and heated under reflux for 18 hours. The mixture was allowed to cool and diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with 0.1M sodium hydroxide solution (50 ml) and water (50 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue purified by chromatography on a Mega Bond Elut column, eluting with 25% ethyl acetate in hexane. Fractions containing the required product were combined and evaporated to dryness to give 4'-hydroxy- N-(isobutoxycarbonyl)- N-(3-methoxy-5-methylpyrazin-2-yl)-2-biphenylsulphonamide as a solid (0.85g); 1H NMR (CDCl3): 0.7 (d, 6H), 1.59-1.79 (m, 1H), 2.49 (s, 3H), 3.83 (d, 2H), 3.96 (s, 3H), 5.15 (s, 1H), 6.78 (d, 2H), 7.24-7.38 (m, 3H), 7.50-7.59 (m, 2H), 7.91 (s, 1H), 8.57 (d, 1H); mass spectrum (+ve ESP): 472 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[N:7]=[C:6]2[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[CH3:41])[CH2:30][CH2:29]1)=O.O1CCCC1.B.O>O1CCCC1>[Cl:40][C:36]1[C:35]([CH3:41])=[C:34]([N:31]2[CH2:32][CH2:33][N:28]([CH2:26][CH2:25][C:6]3[C:5]4[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:8]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=4)[N:7]=3)[CH2:29][CH2:30]2)[CH:39]=[CH:38][CH:37]=1
Reactant: COc1ccc(Cn2nc(CC(=O)N3CCN(c4cccc(Cl)c4C)CC3)c3cc(OC)c(OC)cc32)cc1OC
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2nc(CCN3CCN(c4cccc(Cl)c4C)CC3)c3cc(OC)c(OC)cc32)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
1-((5,6-Dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazol-3-yl)acetyl)-4-(3-chloro-2-methylphenyl)piperazine (60.5 g) was suspended in tetrahydrofuran (1000 ml). Then 1.0 mol-borane tetrahydrofuran complex tetrahydrofuran solution (500 ml) was added thereto and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and water (30 ml) was added to thereby decompose the excessive reagent. After evaporation of the tetrahydrofuran under reduced pressure, conc. hydrochloric acid (300 ml) was added and the mixture was stirred at 50° C. for 1 hour. The aqueous layer was returned to room temperature and made alkaline with potassium carbonate. Then it was extracted with chloroform (3000 ml) and the organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue thus obtained was purified by using a silica gel column (chloroform/ethanol=40/1). Thus a colorless solid (50.0 g) was obtained. This product was recrystallized from ethanol to give 46.3 g of colorless prism crystals (m.p.: 148°-150° C.)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=1)#[CH:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([N:24]=[N+:25]=[N-:26])[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([N:24]2[C:1]([C:3]3[CH:8]=[CH:7][C:6]([N:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=3)=[CH:2][N:26]=[N:25]2)[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21]
Reactant: C#Cc1ccc(N(C)C)cc1
Reactant: COc1cc(N=[N+]=[N-])cc(OC)c1OC
Product: COc1cc(-n2nncc2-c2ccc(N(C)C)cc2)cc(OC)c1OC
Temperature: 80 °C

Procedure:
To a scintillation vial was added (4-ethynyl phenyl)-dimethyl amine (660 5 mmol) and 3,4,5-trimethoxyphenyl azide (1.05 g.; 5 mmol) and the mixture was heated at 80° C. for 24 hours. The crude mixture was purified by column chromatography to give 1-(3,4,5-trimethoxy-phenyl)-5-[4-(N,N-dimethylamino)-phenyl]-1H-[1,2,3]triazole.
Reaction SMILES: [Li]CCCC.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([F:25])[CH:15]=2)=[CH:10][CH:9]=1)[CH3:7].[CH:26](N1CCOCC1)=[O:27]>C1COCC1.ClCCl.Cl>[CH2:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=3)=[C:16]([F:25])[CH:15]=2)=[CH:12][CH:13]=1)[CH3:7]
Reactant: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2)cc1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(-c3ccc(C=O)[se]3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
27.5 ml (0.16 mol) of TMP are initially introduced at −20° C. in 100 ml of THF, and 100 ml (0.16 mol, 15% soln. in hexane) of n-BuLi are metered in. After 30 min at this temperature, a solution of 50.2 g (0.15 mol) of 2-(4′-ethyl-3-fluorobiphenyl-4-yl)selenophene in 400 ml of THF is added. When the addition is complete, the batch is warmed to RT and left at this temperature for 30 min. The solution is cooled to −70° C., and 17.0 ml (0.17 mol) of N-formylmorpholine are added. The reaction mixture is warmed to RT and stirred for 1 h. the solution is diluted with a lot of dichloromethane, and 2 N hydrochloric acid is added. The mixture is washed with water, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phases are washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is taken up in dichloromethane and purified by column chromatography (SiO2, toluene). The further purification is carried out by recrystallisation from toluene. 5-(4′-Ethyl-3-fluorobiphenyl-4-yl)selenophene-2-carbaldehyde is obtained as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH2:15][CH2:16][CH:17]=[CH2:18])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:6][CH2:7]C=C)[CH3:2]>ClCCl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH2:1]([O:3][C:4]([C:5]1([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:7][CH:18]=[CH:17][CH2:16][CH2:15]1)=[O:19])[CH3:2]
Reactant: C=CCCC(CCC=C)(C(=O)OCC)c1cccs1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)C1(c2cccs2)CCC=CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.9 %

Procedure:
To 2-but-3-enyl-2-thiophen-2-yl-hex-5-enoic acid ethyl ester (Example 5a) (3.18 g) in dichloromethane (100 mL) was added Grubbs Catalyst (2nd Generation, Sigma-Aldrich Company Ltd) (0.100 g). The mixture was warmed to reflux under nitrogen. After 20 hours the mixture was allowed to cool to room temperature and evaporated to an oil. Purification by column chromatography on silica eluting with ethyl acetate/isohexane (10:90) to yield the sub-titled compound (2.60 g) as a coloured oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]([CH3:28])=O>>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH:26]([CH3:28])[CH3:25])[CH2:16][CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CCCC1CCNCC1)c1ccccc1
Reactant: CC(C)=O
Product: CC(C)N1CCC(CCCC(NC(=O)OC(C)(C)C)c2ccccc2)CC1

Procedure:
Using alkylation method A, crude N-[1-phenyl-4-(piperidine-4-yl)butyl]carbamic acid tert-butyl ester (0.70 mmol) and acetone (1.5 mL, 20 mmol) afforded the title compound as a crude residue that was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:28]=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:30]=1[OH:31])[C:8]([O:10][C:11]1[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]=1[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([NH2:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:36]([NH:54][C:15](=[O:16])[C:14]1[CH:18]=[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]([O:10][C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:30]([OH:31])=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:28]=2)=[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:13]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: CC(C)(C)c1cc(C(=O)Oc2c(C(C)(C)C)cc(C(=O)Cl)cc2C(C)(C)C)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)c1cc(C(C)(C)C)c(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C(C)(C)C)c1

Procedure:
10.10 grams of 4-(3,5-di-tert.butyl-4-hydroxybenzoyloxy)-3,5-di-tert-butylbenzoyl chloride 5.4 grams of n-octadecylamine and 2.0 grams of triethylamine were heated together in about 100 ml of toluene for about 5 hours at 90° to 98°C. The precipitated triethylamine hydrochloride was filtered. The filtrate was washed with water and dried over anhydrous sodium sulfate. The dried toluene solution was concentrated to remove toluene under reduced pressure yielding 14.5 grams of the product. The product was crystallized twice from acetonitrile and melted at 139° to 140°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]([NH:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[S:5][CH:6]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC=CC=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([N:17]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH2:8][O:9][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:12])[CH3:11])[S:5][CH:6]=1
Reactant: CC(C)CCNC(CO[Si](C)(C)C(C)(C)C)c1cc(Br)cs1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)CCN(C(CO[Si](C)(C)C(C)(C)C)c1cc(Br)cs1)S(=O)(=O)c1ccccc1
Temperature: 75 °C

Procedure:
N-[1-(4-bromothiophen-2-yl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-3-methylbutan-1-amine (248 mg, 0.610 mmol) and DMAP (3.7 mg, 0.031 mmol) were dissolved in 2 mL pyridine and benzenesulfonyl chloride (234 μl, 1.830 mmol) was added. The resulting mixture was heated at 75° C. overnight, after which the mixture was cooled to room temperature, toluene was added and the mixture was concentrated in vacuo. The title compound was purified on silica gel (EtOAc/hexanes).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:10]1([C:2]2[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=2)[CH2:12][CH2:11]1
Reactant: OB(O)C1CC1
Reactant: CNc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CNc1ccc(C2CC2)cc1
Yield: 67.7 %

Procedure:
To a suspension of 4-bromo-N-methylaniline (500 mg, 2.69 mmol), cyclopropylboronic acid (462 mg, 5.38 mmol), (cyclohexyl)3P+HBF4− (99 mg, 0.27 mmol) and K3PO4 (2.0 g, 9.4 mmol) in toluene (20 mL) and H2O (1 mL) was added Pd(OAc)2 (36 mg, 0.16 mmol) at r.t. under N2. The reaction was stirred at reflux overnight. The reaction was filtered, concentrated, and purified by silica gel chromatography (PE:EtOAc=10:1) to give 268 mg (68%) of the title compound as a brown oil. [M+H] Calc'd for C10H23N, 148. Found, 148.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=O.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)C.C([BH3-])#N.[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([CH:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH3:1])=[CH:5][CH:6]=1
Reactant: C1CCNCC1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Solvent: O
Product: CC(c1ccc(Br)cc1)N1CCCCC1
Reaction time: 18 h

Procedure:
4-Bromoacetophenone (1.95 g), piperidine (0.97 ml) and titanium(IV) isopropoxide (3.64 ml) were stirred under argon at room temperature for 1 h. Ethanol (10 ml) was added, followed by sodium cyanoborohydride (0.41 g) and mixture stirred for 18 h. Water (2 ml) was then added and the mixture stirred for 20 minutes. The resulting inorganic precipitate was filtered off, washed with ethanol (20 ml) and the combined organic phase was concentrated in vacuo, redissolved in toluene and purified by Bondelute® chromotography, eluting with 0–20% ethyl acetate/iso-hexane to give the product as a pale yellow oil (1.07 g).