Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[CH2:25][NH2:26].CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[CH2:25][NH:26][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CC1(c2ccc(F)nc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2ccc(C3(C)CCOCC3)cn2)c(OC)c1
Temperature: 160 °C
Yield: 51.8 %

Procedure:
To a solution of 2-fluoro-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridine (110 mg, 0.56 mmol) in (2,4-dimethoxyphenyl)methanamine (1016 μL, 6.76 mmol) and DIEA (246 μL, 1.41 mmol) was added potassium carbonate (156 mg, 1.12 mmol). The resulting mixture was heated to 160° C. in an oil bath for 16 h, The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silicagel (ISCO) eluting with 0-100% ethyl acetate in heptane to give N-(2,4-dimethoxybenzyl)-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amine (100 mg, 0.29 mmol, 51.8% yield) as light yellow color solid. LCMS (m/z): 343 (MH+), 0.63 min.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=2)[N:12]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:11]=1.N1C=CC=CC=1.[CH3:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[S:44](Cl)(=[O:46])=[O:45])(=[O:37])=[O:36]>C1CCCCC1.C(OCC)(=O)C>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[S:35]([CH3:34])(=[O:37])=[O:36])(=[O:46])=[O:45])[CH:17]=2)[N:12]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:11]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3[nH]2)c2cc(N)ccc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3[nH]2)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Yield: 94 %

Procedure:
N-[3-(1H-Benzimidazol-2-yl)-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 2 from 130 mg of 3-(1H-benzimidazol-2-yl)-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-ylamine, 5 ml of pyridine and 87 mg of 2-methylsulfonylbenzenesulfonyl chloride. 192 mg of N-[3-(1H-benzimidazol-2-yl)-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of an orange lac (Rf=0.53, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (50/50 by volume), mass analysis: Cl: m/z 598 (M+H)+.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16][SH:17])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:28]([S:31][CH2:32][CH:33]([CH3:37])[C:34](Cl)=[O:35])(=[O:30])[CH3:29]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16][S:17][C:34](=[O:35])[CH:33]([CH3:37])[CH2:32][S:31][C:28](=[O:30])[CH3:29])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CC(CS)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SCC(C)C(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Reaction time: 8 h

Procedure:
To a mixture of 3 g (0.01M) of N-(3-mercapto-2-methyl propanoyl)-N-cyclopentyl glycine-t-butyl ester, 1.2 g (0.012M) triethylamine in 100 ml methylene chloride was added a solution of 1.8 g (0.01M) of 3-acetylthio-2-methyl propanoyl chloride and stirring continued for 8 hours. It was then washed with water, dried over MgSO4 and evaporated to dryness leaving an oily residue which was purified by HPLC using ethyl acetate-hexane (1:3) as eluent.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]=1[F:17])=[O:4].[OH-].[Na+].Cl>C1COCC1>[F:17][C:6]1[CH:7]=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
Combine methyl 2-fluoro-4-bromobenzoate (1.25 g, 5.36 mmol), phenylboronic acid (1.30 g, 10.72 mmol) and CsF (2.02 g, 13.40 mmol) in DMF (25 mL) and water (3.0 mL) with stirring. Place the hetereogeneous reaction mixture open to the air in an oil bath maintained at 80° C. After 5 minutes of heating, add Pd(OAc)2 (120 mg, 0.536 mmol) in one portion and stir until reaction turns black. Cool reaction to room temperature, dilute with ethyl acetate and filter through a short plug of celite with additional ethyl acetate. Wash organics with water, dry over MgSO4, filter and evaporate. Purification by flash column chromatography yields 3-fluorobiphenyl-4-carboxylic acid methyl ester as a solid. Dissolve the purified ester in THF (0.25M) and add an equal volume of 1 M NaOH. Stir vigorously at room temperature for 15 hours. Upon completion, acidify the reaction with conc. HCl and extract with ethyl acetate. Evaporation of the solvent yields 965 mg (84%) of the title compound. MS (m/e): 214.9 (M−).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br-].[C:12]([CH:15](C)[CH2:16][CH2:17][CH2:18][CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:14])=[O:13]>C1COCC1>[C:2]1(/[CH:1]=[CH:19]\[CH2:18][CH2:17][CH2:16][CH2:15][C:12]([OH:14])=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCCC/C=C\c1ccccc1
Reaction time: 8 h

Procedure:
Benzaldehyde (6.63 g, 0.062 mol, 6.35 ml) in dry THF (20 ml) was added dropwise to a stirred suspension of NaH (60% dispersion, 5.51 g, 0.138 mol) and (5-carboxyhexyl)-triphenylphosphonium bromide (30 g, 0.066 mol) in dry THF (260 ml). After stirring overnight, the solvent was evaporated to dryness, and the residue taken up into water (300 ml). The solution was made alkaline (pH 12-14) with NaOH solution (4 M) and extracted with EtOAc. The basic solution was then acidified (conc. HCl), extracted with Et2O, and the combined extracts washed with brine and dried with MgSO4. Removal of the solvent afforded 16.5 g of crude product which was purified by chromatography (silica, 1:5 EtOAc/petroleum ether, increasing to 1:1 EtOAc/petroleum ether toward completion) to give 10.81 g (85%) of E-/Z-7-phenylhept-6-ene-oic acid (˜1:1 mixture) as a pale yellow oil. Hydrogenation of the unsaturated acid (10% Pd—C, EtOAc) afforded the saturated compound (51): 1H NMR (CDCl3) δ 11.57 (br s, 1H), 7.20 (m, 5H), 2.58 (t, J=7.7 Hz, 2H), 2.31 (t, J=7.5 Hz, 2H), 1.61 (m, 4H), 1.33 (m, 4H). 13C NMR (CDCl3), δ 180.8, 142.7, 128.5, 128.4, 125.7, 36.0, 34.2, 31.4, 29.0, 24.7.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH2:7]([Br:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(O)C>[Br-:15].[CH2:7]([N+:4]1[CH:5]=[CH:6][N:2]([CH3:1])[CH:3]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCBr
Reactant: Cn1ccnc1
Solvent: CCO
Product: CCCCCCCC[n+]1ccn(C)c1
Product: [Br-]
Yield: 90.8 %

Procedure:
1 mole of 1-methylimidazole was dissolved in 400 ml of ethanol and 1.2 moles of n-octyl bromide were added. The mixture was then heated to the boiling point for 5 hours. Thereafter, ethanol and excess n-octyl bromide were removed. The residue was purified in ether. In this manner, 250 g of 1-n-octyl-3-methyl-imidazolium bromide were obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[CH2:14]O>N1C=CC=CC=1.C(Cl)Cl.O>[Cl:3][CH2:14][C:6]1[O:5][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=1
Reactant: OCc1cc2ccccc2o1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: ClCc1cc2ccccc2o1
Reaction time: 18 h
Yield: 70.8 %

Procedure:
Thionyl chloride (5.14 mL, 70.46 mmol) was added dropwise to a solution of benzofuran-2-methanol (3.58 g, 23.48 mmol) and pyridine (10 drops) in methylene chloride (60 mL). Stirring was continued at room temperature for 18 hours. The mixture was carefully diluted with water and extracted with methylene chloride. The organic extracts were washed with aqueous sodium bicarbonate, dried (MgSO4) and concentrated to afford crude product which was purified by flash column chromatography (10% EtOAc/hexanes) to afford 2.77 g (69%) of pure product as a yellow oil.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(N(C)C)=C(C)C.[F:15][C:16]([F:32])([F:31])[CH2:17][N:18]1[CH:22]=[C:21]([NH:23][C:24]2([C:29]#[N:30])[CH2:28][CH2:27][O:26][CH2:25]2)[CH:20]=[N:19]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:29]([C:24]1([N:23]([C:21]2[CH:20]=[N:19][N:18]([CH2:17][C:16]([F:31])([F:15])[F:32])[CH:22]=2)[C:1](=[O:6])[CH:2]=[C:3]=[CH2:4])[CH2:28][CH2:27][O:26][CH2:25]1)#[N:30]
Reactant: CC#CC(=O)O
Reactant: N#CC1(Nc2cnn(CC(F)(F)F)c2)CCOC1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C=CC(=O)N(c1cnn(CC(F)(F)F)c1)C1(C#N)CCOC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 68.6 %

Procedure:
As shown in step 24-ii of Scheme 24, to a solution of but-2-ynoic acid (833.6 mg, 9.915 mmol) in DCM (12 mL) at 0° C. was added 1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (1.325 g, 1.312 mL, 9.915 mmol). After stirring for 40 minutes, the reaction mixture was cooled to −78° C. and a solution of 3-[[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]amino]tetrahydrofuran-3-carbonitrile (Compound 2075, 1.72 g, 6.610 mmol) and DIEA (2.563 g, 3.454 mL, 19.83 mmol) in DCM (12 mL) was added. The reaction mixture was warmed to 0° C. (ice-water bath), and after 1 hour the mixture was warmed to 23° C. After 30 min at 23° C., the reaction mixture was partitioned between water and EtOAc (100 mL each). The organics were separated (insoluble precipitate is present), washed with water then brine (100 mL each), dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by medium pressure silica gel chromatography (0-80% EtOAc/hexanes) to provide N-(3-cyanotetrahydrofuran-3-yl)-N-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]buta-2,3-dienamide (Compound 2076, 1.48 g) as a yellow oil: ESMS (M+H) 327.20; 1H NMR (CDCl3, 300 MHz) δ 7.70 (s, 1H), 7.63 (s, 1H), 5.57 (t, J=6, 1H), 5.19 (d, J=6, 2H), 4.77 (q, J=9, 2H), 4.00 (m, 4H), 2.50 (m, 1H), 2.30 (m, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:24][CH2:25][N:26]=[C:27]=[O:28].[Cl-].[NH4+]>ClCCl>[CH3:2][O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH2:24][CH2:25][NH:26][C:27]2=[O:28])[CH:7]=1
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: O=C=NCCCl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cc1cccc(N2CCNC2=O)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Methyl(3-aminophenyl)acetate hydrochloride was suspended in dichloromethane (7 vol) under nitrogen. Diisopropylethylamine (1.04 vol) was added at 20° C. over 30 minutes, and the reaction mixture was stirred for 30 minutes at 20° C. 2-Chloroethyl isocyanate (0.44 vol) was added dropwise at 20° C. over 100 minutes. The reaction mixture was stirred at 20° C. for three hours. A saturated solution of ammonium chloride (5 vol) was added dropwise over 10 mins and the resultant mixture was stirred for ten minutes. The organic phase was separated and washed with water (5 vol). Tetrahydrofuran (2×3 vol) was added and the mixture was concentrated to 2 vol. Dry tetrahydrofuran (5 vol) was added, and the mixture was concentrated to 2 vol. Dry THF (3 vol) was added, under nitrogen at 20° C. The reaction mixture was cooled to 0° C., and potassium tert-butoxide (0.56 wt) was added portion-wise in 5 stages, allowing 20 minutes between two subsequent additions. The reaction mixture was stirred at 20° C. for one hour. Hydrochloric acid (0.5N, 2 vol) was added dropwise over 20 minutes. Ethyl acetate (10 vol) was added and the organic phase was separated. The organic layer was washed with aqueous sodium hydrogencarbonate solution (4%, 2 vol) and brine (2 vol), and the organic layer was then evaporated to dryness under vacuum to give the title compound (overall yield: 90% w/w).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:23][CH3:24])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][O:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[O:9]2)=[CH:4][C:3]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([F:34])[C:27]=1[F:35].[H-].[Na+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[CH2:38]([O:16][C@H:11]1[C@H:12]([O:15][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([O:14][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[C@@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([F:34])[C:27]=3[F:35])[CH:4]=2)([O:23][CH3:24])[O:9][C@@H:10]1[CH2:17][O:18][Si:19]([CH3:21])([CH3:22])[CH3:20])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 210.4 %

Procedure:
(2S,3R,4S,5S,6R)-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-methoxy-6-(trimethylsilyloxymethyl)tetrahydropyran-3,4,5-triol 2h (1.63 g, 2.84 mmol) was dissolved in 30 mL DMF and cooled to 0° C., followed by addition of 60% NaH (570 mg, 14.2 mmol). Then the reaction mixture was warmed to room temperature and stirred for 45 minutes. Thereafter, benzyl bromide (1.7 mL, 14.2 mmol) was added before the reaction mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure after 5 mL methanol were added. After 150 mL ethyl acetate and 50 mL water were added into the residue, the resulting residue was partitioned and the organic extract was washed with water (50 mL), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound [[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]trimethyl-silane 21 (2.4 g, yellow grease), with yield: 100%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.[CH3:11][N:12]([CH3:16])[C:13](Cl)=[O:14].C(N(CC)CC)C>ClCCl>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[O:10][C:13](=[O:14])[N:12]([CH3:16])[CH3:11])#[N:7]
Reactant: N#Cc1ccc(F)cc1O
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cc(F)ccc1C#N
Yield: 67 %

Procedure:
Under N2, a stirred solution of 4-fluoro-2-hydroxybenzonitrile (685 mg, 5.00 mmol), dimethylcarbamoyl chloride, and triethylamine (606 mg, 6 mmol) in dichloromethane (10 mL) was heated at reflux for 20 hrs. The cooled mixture was diluted with dichloromethane (10 mL) washed with water, and brine. The organic layer was separated, dried (Na2SO4), concentrated, and the residue purified by column chromatography (SiO2, 5% ethyl acetate-CH2Cl2) to provide 700 mg (Yield 67%) of the title compound as a white crystalline solid: 1H NMR (CDCl3, 500 MHz) δ ppm: 3.03 (3H, s, NMe), 3.15 (3H, s, NMe), 6.99 (1H, dt, J=2.5 Hz, 8.5 Hz, Ar—H), 7.23 (1H, dd, J=2.5 Hz, 9.5 Hz, Ar—H), 7.61 (1H, dd, J=9 Hz, 6 Hz, Ar—H); 13C NMR (CDCl3, 125.77 Hz) δ ppm: 36.76, 37.06, 102.84, 102.86, 111.59, 111.79, 113.24, 113.42, 114.99, 134.36, 134.45, 152.54, 155.06, 155.16, 164.26, 166.31. HRMS (ESI) calcd for C10H10N2O2F (M+H) 209.0726, found 209.0722.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=[O:13].[CH3:15][Si](C=[N+]=[N-])(C)C>CO.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Solvent: CO
Solvent: CCOCC
Product: COC(=O)Cc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Step H (1): To a solution of 2-(5-bromo-1H-indol-3-yl)acetic acid (1.0 g 3.94 mmol) in MeOH (5 mL) and Et2O (15 mL) was added (trimethylsilyl)diazomethane (2.0 M solution in hexanes, 10 mL). The reaction was stirred at rt for 2 h. The solvents were removed and the residue was purified by flash chromatography to yield 900 mg of methyl 2-(5-bromo-1H-indol-3-yl)acetate (yield 85%). 1H NMR (500 MHz, CDCl3) δ ppm 3.71 (s, 3 H) 3.72 (s, 2 H) 7.16 (d, J=2.14 Hz, 1 H) 7.21 (d, J=8.55 Hz, 1 H) 7.27 (dd, J=8.55, 1.83 Hz, 1 H) 7.72 (d, J=1.53 Hz, 1 H) 8.12 (s, 1 H)
Reaction SMILES: C([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:25])[CH2:23][OH:24])=[CH:18][CH:17]=1)(C)(C)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34].CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33]([NH:25][CH:22]([C:19]1[CH:18]=[CH:17][C:16]([C:15]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:27])[OH:5])=[O:26])=[CH:21][CH:20]=1)[CH2:23][OH:24])=[O:34]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(N)CO)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NC(CO)c2ccc(C(=O)Nc3ccccc3NC(=O)O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
To a stirred solution of 299 (88 mg, 0.24 mmol) in dry DCM (2 mL) at −20° C. was added 3,4-dimethoxybenzoyl chloride (50 mg, 0.25 mmol) followed by Et3N (37 μL, 0.26 mmol). The reaction mixture was allowed to warm up to room temperature then was stirred for 48 h. A solution of sat. NH4Cl was added, followed by DCM and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/DCM: 4/96) to afford title compound 300 (91 mg, 0.17 mmol, 71% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.29 (s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.65-7.58 (m, 1H), 7.46 (m, 7H), 6.80 (d, J=8.1 Hz, 1H), 5.20-5.10 (m, 1H), 3.95-3.78 (m, 2H), 3.88 (s, 3H) 3.84 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:27][C:28]1([CH3:42])[O:33][C:32]2[CH:34]=[CH:35][C:36]([C:38]([OH:40])=O)=[CH:37][C:31]=2[C:30](=[O:41])[O:29]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:38]([C:36]3[CH:35]=[CH:34][C:32]4[O:33][C:28]([CH3:27])([CH3:42])[O:29][C:30](=[O:41])[C:31]=4[CH:37]=3)=[O:40])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCNCc1ccc(C#Cc2ccc(CCCC)cc2)cc1
Reactant: CC1(C)OC(=O)c2cc(C(=O)O)ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)C(=O)c1ccc2c(c1)C(=O)OC(C)(C)O2
Yield: 47.7 %

Procedure:
A solution of N-{4-[(4-butylphenyl)ethynyl]benzyl}-1-hexanamine (144 mg, 0.41 mmol), 2,2-dimethyl-4-oxo-4H-1,3-benzodioxine-6-carboxylic acid (92 mg, 0.41 mmol), EDC.HCl (87 mg, 0.46 mmol), HOBT (61 mg, 0.46 mmol) and DIEA (105 μL, 0.62 mmol) in DCM (10 mL) was stirred at rt overnight. Then the reaction mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3, a saturated aqueous solution of NH4Cl and brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silicagel (EtOAc/c-Hex (20/80)) to give 108 mg (47%) of the title compound as a colorless oil. HPLC, Rt: 6.14 min (purity: 99.9%). 1H NMR (CD3Cl3) δ: 0.82 (m, 3H), 0.91 (t, J=7.3 Hz, 3H), 1.32-1.40 (m, 10H), 1.57 (m, 2H), 1.72 (s, 6H), 2.59 (t, J=7.6 Hz, 2H), 3.16-3.41 (m, 2H), 4.40-4.72 (m, 2H), 7.00 (m, 2H), 7.14 (d, J=8.3 Hz, 2H), 7.25 (m, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.61 (m, 1H), 8.03 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:16]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:18])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH:16]([CH3:18])[CH3:17])=[CH:21][CH:22]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(-c3ccc(OC(C)C)cc3)ccc2[nH]1

Procedure:
The sub-title compound was prepared in accordance with Example 1(a) form 5-bromoindole-2-carboxylic acid ethyl ester and 4-isopropoxyphenylboronic acid.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C.CCOC(C)=O>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 52.6 %

Procedure:
Under nitrogen dissolve 1-benzhydrylazetan-3-ol (5 g, 20.9 mmol), imidazole (3.5 g, 52.25 mmol) in anhydrous DMF (25 mL). Cool solution in an ice bath, add slowly tert-butyldimethylsilyl chloride (50 wt. % solution in toluene, 6.3 g, 41.8 mmol). Stir at RT for 22 h. Dilute with EtOAc and wash with saturated aqueous sodium bicarbonate solution. Separate organic layer, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 EtOAc:hexanes) to give the title compound (3.89 g, 53%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:10]=[C:11](Cl)[C:12]2[CH:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:15][C:13]=2[N:14]=1.C(O)=O>O1CCOCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:8][C:9]1[N:10]=[CH:11][C:12]2[CH:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:15][C:13]=2[N:14]=1
Reactant: COC(=O)C1CCc2nc(N)nc(Cl)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COC(=O)C1CCc2nc(N)ncc21
Temperature: 100 °C

Procedure:
Triethylamine (3.20 mL, 23.0 mmol) was added to a solution of methyl 2-amino-4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylate (2.11 g, 9.27 mmol) in dioxane (42 mL) followed by formic acid (0.89 mL, 22.28 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (660 mg, 0.902 mmol). The reaction mixture was heated at 100° C. in a sealed tube overnight. The solvent was evaporated. The residue was purified by chromatography on silica (220 g+125 g cartridges) using CH2Cl2: MeOH 95:5 to afford the title compound which was used without further purification in the next step.