Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:13][C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[C:35](=[O:43])[C:36](=[O:42])[C:37]=2[O:38][CH:39]([CH3:41])[CH3:40])=[CH:24][CH:23]=1>CN(C)C=O>[CH2:1]([C:3]1[N:13]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[C:35](=[O:43])[C:36](=[O:42])[C:37]=3[O:38][CH:39]([CH3:41])[CH3:40])=[CH:26][CH:27]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: CC(C)Oc1c(-c2ccccc2-c2ccc(CBr)cc2)c(=O)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2c(OC(C)C)c(=O)c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (0.66 g; preparable as described in Mantio et al, J. Med. Chem. 34, (1991), pp 2919/2922 and in EP-A-0400914; Merck), and anhydrous potassium carbonate (1.02 g) were added to a solution of 3-(4'-bromomethylbiphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione (1.88 g; preparable as described in Example 1(c)) in dry dimethylformamide (10 ml) and the resulting mixture was stirred at ambient temperature for approximately 16 hours. More 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (0.33 g) was added to the dark reaction solution obtained, and stirring was continued at ambient temperature for an additional 24 hours. The resulting dark mixture was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was then separated, washed with water (50 ml), and dried over magnesium sulphate. The resulting solution was evaporated to leave a dark oil which was purified by flash chromatography on silica gel (eluting with 1% industrial methylated spirit in dichloromethane) followed by flash chromatography on silica gel (eluting with ethyl acetate) and flash chromatography on silica gel (eluting with 0% rising to 2% methanol in dichloromethane) to give 3-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl -2-yl]-4-isopropoxycyclobut-3-ene-1,2-dione, an active compound of the present invention, as a yellow foam (0.176 g) which melted slowly at 60° C. or above.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>C(#N)C>[Cl:42][C:43]1[CH:44]=[C:45]([S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc(Cl)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 39.8 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0306 g, 0.0663 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-chlorobenzenesulfonyl chloride (0.0275 mL, 0.195 mmol) to obtain 4-(3-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0168 g, yield 40%).
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]2[O:7][C:8]([CH3:34])([CH3:33])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:31])[CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[CH:13][C:12]3=[O:32])[C:5]=2[CH:4]=1)#[N:2].[O:37]([C:44](Cl)=[S:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])O.[Na+]>C(#N)C.CN(C)C1C=CN=CC=1>[C:1]([C:3]1[CH:36]=[CH:35][C:6]2[O:7][C:8]([CH3:34])([CH3:33])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([O:31][C:44]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[S:45])[CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)=[CH:13][C:12]3=[O:32])[C:5]=2[CH:4]=1)#[N:2]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: COc1ccc(COCCCC(O)c2ccn(C3=CC(C)(C)Oc4ccc(C#N)cc43)c(=O)c2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(COCCCC(OC(=S)Oc2ccccc2)c2ccn(C3=CC(C)(C)Oc4ccc(C#N)cc43)c(=O)c2)cc1

Procedure:
In 30 ml of anhydrous acetonitrile, is dissolved 1.42 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-hydroxy-4-p-methoxybenzyloxybutyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 44. Then, 1.50 g of 4-dimethylaminopyridine and 0.81 ml of phenoxythiocarbonyl chloride are added to the solution at room temperature, and reacted at that temperature for 8 hours. After stopping the reaction by adding 0.1M aqueous solution of sodium hydrogen carbonate, the reaction mixture is extracted with ether. The organic layer is washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/2 mixture of ethyl acetate/n-hexane as a developing solvent. Thus, 1.61 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-phenoxythiocarbonyloxy-4-p-methoxybenzyloxybutyl)-1-pyridinyl}-2H-benzo[b]pyran is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[H-].[Na+].Cl[CH2:15][O:16][CH3:17].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1.C(OCC)(=O)C>[CH3:15][O:16][CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH2:7][OH:9])[CH:10]=1
Reactant: Cc1ccc(O)cc1C(=O)O
Reactant: COCCl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1ccc(C)c(CO)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
5-Hydroxy-2-methyl-benzoic acid (2 g, 13.3 mmol) was dissolved in tetrahydrofuran (40 ml). The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in mineral oil) (1.8 g, 39.5 mmol) was added portionwise. Chloro(methyloxy)methane (4 ml, 52 mmol) was added. The reaction mixture was stirred for 30 min at 0° C. The mixture was poured into ice and extracted with ethyl acetate, two phases were separated and the organic layer was dried over Na2SO4 and evaporated under vacuum to give the crude product as a yellow oil. To this material, dissolved in THF (20 ml), cooled at 0° C., LiAlH4 1M in THF (15 ml, 15 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 30 min. After this time the reaction mixture was poured into ice and diluted with 60 ml of ethyl acetate. Phases were separated, the organic phase was dried over Na2SO4 and evaporated under vacuum to afford a colorless oil that was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 75:25 as eluents affording the title compound (1.9 g) as a colorless oil.
Reaction SMILES: C=O.[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][S:10][C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12]2)=[CH:7][CH:6]=1.[C:22]([BH3-])#N.[Na+].[OH-].[Na+].[Cl-].[Na+]>C(#N)C.C(O)(=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][S:10][C@@H:11]2[CH2:15][N:14]([CH3:22])[C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12]2)=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
3.43 ml of 35% formalin were added to a solution of 2.25 g of (2S, 4S)-4-(4-methoxybenzylthio)-2-methoxycarbonylpyrrolidine dissolved in 42 ml of acetonitrile. Subsequently, 804 mg of sodium cyanoborohydride were divided into three portions and added to the mixture over a period of 5 minutes. The mixture was then stirred at room temperature for 30 minutes. At the end of this time, the mixture was cooled, 1.3 ml of acetic acid was added, and the reaction mixture was stirred at room temperature for 40 minutes. 40 ml of a 1N aqueous solution of sodium hydroxide and an aqueous solution of sodium chloride were then added to the mixture, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by a similar procedure to that described in Preparation 4-(10), to afford 1.31 g of the title compound as an oil. The infra-red spectrum, nuclear magnetic resonance spectrum and thin layer chromatograph of this compound were identical to those of the compound prepared as described in Preparation 4-(10).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]3[CH:23]=[CH:24][S:25][C:15]=23)[CH2:9][CH2:8]1)(=[O:4])=[O:3]>[Pd].CO>[CH3:1][S:2]([CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:19]([NH2:20])=[CH:18][N:17]=[C:16]3[CH:23]=[CH:24][S:25][C:15]=23)[CH2:9][CH2:8]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)CC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reaction time: 2 h

Procedure:
A mixture of N-{trans-4-[2-(methylsulfonyl)ethyl]cyclohexyl}-6-nitrothieno[3,2-b]pyridin-7-amine (220 mg, 0.57 mmol) and 10% palladium on carbon (60 mg, 0.06 mmol) in methanol (4 mL) was hydrogenated under balloon pressure of H2 at room temperature for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give the desired product, which was used in the next step directly. LCMS calculated for C16H24N3O2S2 (M+H)+: m/z=354.1. Found: 354.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[C:5]([Cl:10])=[C:4]([CH3:11])[N:3]=1.[OH-].[K+].[N+:14]([C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[C:19]([C:26]([F:29])([F:28])[F:27])[C:18]=1Cl)([O-:16])=[O:15]>CN(C)C=O>[Cl:8][C:7]1[C:2]([NH:1][C:18]2[C:19]([C:26]([F:28])([F:29])[F:27])=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])=[N:3][C:4]([CH3:11])=[C:5]([Cl:10])[C:6]=1[CH3:9]
Reactant: Cc1nc(N)c(Cl)c(C)c1Cl
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(Nc2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)c(Cl)c(C)c1Cl

Procedure:
In 20 ml. of dimethylformamide, 1.9 g. of 2-amino-3,5-dichloro-4,6-dimethylpyridine was dissolved and 0.7 g. of powdery potassium hydroxide was gradually added with stirring and a solution of 2.7 g. of 2,4-dinitro-6-trifluoromethylchlorobenzene in 10 ml. of dimethylformamide was added dropwise at room temperature to react them for about 10 hours. The reaction mixture was treated as the process of Preparation No. 7 to obtain 1.6 g. of the object compound having the melting point of 131° to 133° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=1[F:44]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:7]([O:8][C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=2[F:44])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)c(O)c1F
Reactant: N#Cc1ccc(Br)c(F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)c(Oc2ccc(C#N)cc2F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-methylphenol (3.25 g, 20.24 mmol) and 18-crown-6 (0.535 g, 2.024 mmol) in DMSO (40 ml) was added potassium tert-butoxide (20 wt % in THF) (12.49 g, 22.26 mmol) and the reaction mixture was stirred at rt for 30 minutes. Next, 4-bromo-3-fluorobenzonitrile (4.05 g, 20.24 mmol) was added and the reaction mixture stirred at 135° C. for 3 days. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-3-fluorobenzonitrile (4.56 g, 16.30 mmol, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05 (dd, 1H), 7.59 (d, 1H), 7.35-7.43 (m, 1H), 7.30 (t, 1H), 6.89 (t, 1H), 2.24 (d, 3H).
Reaction SMILES: COC1C=CC(C[N:10]2[C:14]3([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH:13]3[CH2:12][O:11]2)=CC=1.FC(F)(F)C(O)=O>ClCCl>[N:28]1[CH:27]=[CH:26][C:25]([C:14]23[CH2:15][NH:16][CH2:17][CH:13]2[CH2:12][O:11][NH:10]3)=[CH:30][CH:29]=1
Reactant: COc1ccc(CN2OCC3CN(C(=O)OC(C)(C)C)CC32c2ccncc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(C23CNCC2CON3)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of tert-butyl 1-[(4-methoxyphenyl)methyl]-6a-(4-pyridyl)-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (1.3 g, 3.16 mmol) in dichloromethane (30 mL) is added trifluoroacetic acid (7 mL, 94.77 mmol). The resulting solution is stirred at room temperature for 1 hour. The reaction is concentrated and the resulting residue is kept at room temperature overnight. This residue is then loaded onto an ion exchange column and the column is first eluted with methanol followed by 2 M ammonia/methanol solution. The desired basic fraction is collected and concentrated under reduced pressure to give the title compound (592 mg, 98%). ES/MS (m/e): 192 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:27]5[CH:28]=[N:29][CH:30]=[C:25]([CH3:24])[CH:26]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: Cc1cncc(B(O)O)c1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: Cc1cncc(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)c1
Yield: 17 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 5-methylpyridin-3-ylboronic acid were reacted to give 191 (0.027 g, 17%). 1H NMR (400 MHz, DMSO) δ 8.73 (d, J=2.4, 2H), 8.42 (s, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.69 (dd, J=8.4, 2.3, 1H), 7.20 (d, J=8.4, 1H), 5.82 (dt, J=13.1, 6.5, 1H), 4.43 (t, J=4.8, 2H), 3.56-3.39 (m, 2H), 2.39 (s, 3H), 1.58 (d, J=6.6, 6H). MS (ESI(+)): m/z 404.0 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>>[Br:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([Br:1])[CH:9]=1)[O:11][C:12](=[O:14])[CH:13]=[CH:5]2
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc(Br)cc(Br)c1O
Solvent: CCN(CC)CC
Product: O=c1ccc2cc(Br)cc(Br)c2o1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
To a suspension of 3,5-dibromosalicylaldehyde (100 g, 357 mmol) in acetic anhydride (164.8 mL, 1.8 mol) was added triethylamine (45 mL, 375 mmol). The reaction solution was heated overnight at reflux under argon. The solution was cooled to room temperature and a solid mass formed. The dark brown reaction mixture was washed with hot hexanes (3×300 mL) and aqueous saturated sodium bicarbonate. The resulting solid was dissolved in EtOAc (2L) and washed with water. The organic layer was dried (sodium sulfate) and concentrated to give a brown solid that was collected by filtration. The solid was dried in vacuo to give substantially pure 6,8-dibromocoumarin (94.2 g, 87% yield).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Li]CCCC.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.Cl>>[B:13]([OH:18])([OH:14])[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7]
Reactant: Cc1ccsc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Product: Cc1ccsc1B(O)O
Yield: 93 %

Procedure:
2-Bromo-3-methylthiophene was treated with n-BuLi (1.6 M in hexanes, 38.8 mL, 62.1 mmol), triisopropyl borate (15.1 mL, 65.4 mmol) and HCl(aq) (2.7 N, 52.5 mL) as for 1 to give the title compound 5 (7.2 g, 93% yield) as a brown solid: 1H NMR (CD3OD) δ 7.27 (d, J=5.5 Hz, 1H), 6.80 (d, J=5.5 Hz, 1H), 2.16 (s, 3H). This material was used directly in Suzuki cross coupling reactions.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:3]1[C:4]2[C:9](=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: OB(O)c1cccs1
Reactant: O=Cc1ccc2cn[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc2c(-c3cccs3)n[nH]c2c1
Yield: 70.6 %

Procedure:
A mixture of 1H-indazole-6-carbaldehyde (50 mg, 0.18 mmol), thiophen-2-ylboronic acid (47 mg, 0.37 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol) and 2M Na2CO3 (0.28 mL, 0.55 mmol) in DME/H2O (2 mL/1 mL) was heated under reflux for 16 hours. The crude reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel using EtOAc (10 to 20%) in DCM as the eluent to provide the title compound as a pale yellow solid (29 mg, 70%). 1H NMR (400 MHz, CD3OD) δ ppm 10.09 (s, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.09 (s, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.69 (d, J=3.8 Hz, 1H), 7.48 (d, J=5.0 Hz, 1H), 7.19 (dd, J=4.8, 3.8 Hz, 1H); MS ESI 229.0 (100) [M+H]+, calcd for [C12H8N2OS+H]+ 229.04.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:26])[CH2:11][CH2:12][CH2:13][C:14]([CH3:25])=[CH:15][CH2:16][CH2:17][C:18]([O:20][Si](C)(C)C)=[CH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:32]N1C(=O)CCC1=O.CCOCC>O1CCCC1.[Cl-].[Na+].O>[CH2:1]([O:8][CH2:9][CH:10]([CH3:26])[CH2:11][CH2:12][CH2:13][C:14]([CH3:25])=[CH:15][CH2:16][CH2:17][C:18](=[O:19])[CH2:20][Br:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CCC=C(C)CCCC(C)COCc1ccccc1)O[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=CCCC(=O)CBr)CCCC(C)COCc1ccccc1
Reaction time: 4 h
Yield: 108.7 %

Procedure:
11-Benzyloxy-6,10-dimethyl-2-trimethylsiloxy-undec-1,5-diene (15.36 g, 41 mM) in dry tetrahydrofuran (400 ml) is treated with sodium bicarbonate (4.1 g, 49 mM) and N-bromosuccinimide (7.3 g, 41 mM) at -70° C. and allowed to stir for 4 hours. The reaction mixture is allowed to reach room temperature after which saturated sodium bicarbonate, ether and brine are added. The phases are separated, the aqueous phase is extracted with ether and the combined organic extracts are washed with brine and dried (Na2SO4). The solvent is removed in vacuo to give crude 11-benzyloxy-1-bromo-6,10-dimethyl-2-oxo-undec-5-ene (17 g).
Reaction SMILES: CN(CCN(C)C)C.[CH3:9][C:10]([CH3:28])([CH3:27])[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=1.[Li]CCCC.CN([CH:37]=[O:38])C>CCOCC>[CH3:9][C:10]([CH3:28])([CH3:27])[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:15]=1[CH:37]=[O:38]
Reactant: CC(C)(C)CCOc1cccc(OCCC(C)(C)C)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)CCOc1cccc(OCCC(C)(C)C)c1C=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
TMEDA (23.0 g, 0.198 mol), 1,3-di(3,3-dimethylbutoxy)benzene (46.2 g, 0.166 mol) and ether (500 mL) were brought together in a two-neck 1-L flask fitted with a nitrogen inlet and a pressure-equalizing addition funnel. The reaction mixture was cooled to 0° C., and deaerated. n-BuLi (2.5 M solution in hexanes, 0.18 mol) was added dropwise over a period of 30 min via the addition funnel. The mixture was stirred for 3 h, following which that time it was warmed to room temperature. At this point DMF (23.0 g, 0.315 mol) was added dropwise; after 2 h of stirring, the reaction was quenched with water, extracted with ether (4×300 mL), separated, and evaporated. The product was purified by chromatography on silica using 9:1 hexanes:ethyl acetate as the eluant, giving 36.6 g of product (72% yield, based on 46.2 g of the 1,3-di(3,3-dimethylbutoxy)benzene starting material). 1H NMR (250 MHz, CDCl3): 10.49 (s, 1H), 7.37 (t, 1H, J=8.5 Hz), 6.52 (d, 2H, J=8.5 Hz), 4.06 (t, 4H, J=7.2 Hz), 1.76 (t, 4H, J=7.2 Hz), 0.96 (s, 18H). HRMS (ESI+) m/z: 329.2107 (calcd for C19H30O3Na (M+Na)+ 329.2092).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH2:28][C:27]1[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[CH2:20][CH3:21]
Reactant: COc1ccc(C=O)cc1
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCN(CCC)CCCCN(Cc1ccc(C#N)cc1)Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
0.570 g (1.98 mmol) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a), 11.4 ml of ethanol, and 0.540 g (3.97 mmol, 2.0 equivalents) of 4-methoxybenzaldehyde were charged in a 50 ml recovery flask under a nitrogen stream. The mixture was then cooled to 0° C. After the addition of 1.009 g (4.76 mmol, 2.4 equivalents) of sodium triacetoxyborohydride, the mixture was stirred at room temperature for 18 hours. After confirming the disappearance of the raw material by TLC, the reaction solution was added to 50 ml of a saturated sodium bicarbonate aqueous solution, and extracted twice with 50 ml of chloroform. The chloroform layer was washed with 100 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (Chromatorex NH, chloroform:n-hexane=1:1), thereby obtaining 0.559 g of 4-{[(4-dipropylaminobutyl)-(4-methoxybenzyl)amino]-methyl}-benzonitrile (19) as a light yellow oily substance (yield: 69.2%). [HPLC: 99.4% (HPLC measurement conditions B)]