Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH2:12]([O:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:12]([O:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:22][C:21]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)c(Br)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cc(C(=O)OCc3ccccc3)ccc2OCc2ccccc2)cc1
Yield: 5.6 %

Procedure:
To a degassed solution of 4-methoxybenzeneboronic acid (5.0 g, 32.9 mmol), benzyl 4-benzyloxy-3-bromobenzoate (12.1 g, 30.5 mmol), and potassium carbonate (10.4 g, 76.2 mmol) in toluene/ethanol 2/1, (140 mL), Pd(PPh3)4 (400 mg, 1 mol %) was added and the mixture is degassed for further 5 minutes. The mixture is then refluxed for 12 hours. The mixture was partitioned between ethyl acetate and water and extracted. The organic solvent was dried over sodium sulphate, removed under reduced pressure, and the residue purified by column chromatography (9/1 DCM/hexane) to afford 0.73 g of pure title compound, 9.74 g of a 4:6 mixture of title compound and the corresponding ethyl ester, and 0.71 g of the ethyl ester derivative.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:25](=[O:26])[N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:23]=[CH:22]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:25](=[O:26])[N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:23]=[CH:22]4)=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CCCCCn1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Agent: Br
Product: CCCCCn1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Yield: 89 %

Procedure:
This compound was synthesized as a white amorphous solid from 4g (43.4 mg, 0.103 mmol) in 48% aqueous HBr (1.0 mL) in 89% yield by following general procedure 1.4: 1H NMR (400 MHz, CDCl3, δH) 7.62 (s, 1H), 7.40 (t, J=10.1 Hz, 2H), 7.05-6.94 (m, 4H), 6.75 (d, J=8.5 Hz, 2H), 3.85 (t, J=7.2 Hz, 2H), 3.48-3.40 (m, 4H), 3.43-3.35 (m, 4H), 1.90-1.72 (m, 2H), 1.40-1.33 (m, 4H), 0.91 (t, J=6.9 Hz, 3H). MALDI-MS: 408.2 (M+H+), 430.2 (M+Na+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][C:14]([N:16]3[CH2:19][CH:18]([OH:20])[CH2:17]3)=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.CC(C)=O.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:16]3[CH2:19][CH:18]([OH:20])[CH2:17]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(COCCc1ccc2sccc2c1)N1CC(O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: OC1CN(CCOCCc2ccc3sccc3c2)C1
Temperature: 5 °C
Reaction time: 17 h

Procedure:
1.20 g of 2-(2-(1-benzothiophene-5-yl)ethoxy)acetic acid was dissolved in 12 ml of methylene chloride. Thereafter, 2.3 ml of triethylamine and 0.38 g of imidazole were added to the obtained solution, and the mixture was then cooled to 5° C. Thereafter, 0.41 ml of thionyl chloride was added dropwise thereto, and the obtained mixture was stirred at the same above temperature for 1 hour. The reaction mixture was cooled to −60° C., and thereafter, 0.82 ml of triethylamine and 0.72 g of 3-azetidinol hydrochloride were added thereto. The mixture was stirred at the same above temperature for 1 hour and then at a room temperature for 1.5 hours. Thereafter, water was added to the reaction mixture, and the pH thereof was adjusted to pH 1.0 by addition of 6 mol/l hydrochloric acid. Thereafter, an organic layer was separated. The organic layer was washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent was distilled away under a reduced pressure, so as to obtain a yellow oil product, 2-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-azetidinyl)-1-ethanone. (2) The above 2-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-azetidinyl)-1-ethanone was dissolved in 12 ml of tetrahydrofuran, and the obtained solution was cooled to 5° C. Thereafter, 12.7 ml of a tetrahydrofuran solution containing a 1 mol/l borane-tetrahydrofuran complex was added dropwise thereto, and the obtained mixture was stirred at a room temperature for 17 hours. Thereafter, 10 ml of acetone was added to the reaction mixture, and the obtained mixture was then stirred for 30 minutes. Thereafter, 6.0 ml of 6 mol/l hydrochloric acid was added thereto, followed by heating to reflux for 2 hours. The reaction solution was cooled, and water and ethyl acetate were added to the reaction mixture. The pH thereof was adjusted to pH 13 by addition of a 2 mol/l aqueous sodium hydroxide solution, and an organic layer was then separated. The organic layer was washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent was distilled away under a reduced pressure, so as to obtain 1.13 g of a yellow oil product, 1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-azetidinol.
Reaction SMILES: N[C@@H:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=O.[CH:13]1([NH:20][C:21]([NH2:23])=[S:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:20][C:21]2[S:22][C@H:2]([CH2:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[C:3](=[O:5])[N:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC(=S)NC1CCCCCC1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Product: O=C1N=C(NC2CCCCCC2)S[C@@H]1CC1CCCCC1

Procedure:
Synthesis was performed from (2S)-2-amino-3-cyclohexylpropanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: [N+](C1C=CC(C(O[CH:11]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:15]([CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:14]([CH2:33][O:34][C:35](=[O:45])[C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)[CH2:13][O:12]2)=O)=CC=1)([O-])=O.[F:48][C:49]([F:64])([F:63])[C:50]1[CH:51]=[C:52]([C@H:60]([OH:62])[CH3:61])[CH:53]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:55]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([C:35]([O:34][CH2:33][C@@H:14]2[C@@H:15]([CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C@@H:11]([O:62][C@@H:60]([C:52]3[CH:51]=[C:50]([C:49]([F:63])([F:64])[F:48])[CH:55]=[C:54]([C:56]([F:57])([F:58])[F:59])[CH:53]=3)[CH3:61])[O:12][CH2:13]2)=[O:45])=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: O=C(OCC1COC(OC(=O)c2ccc([N+](=O)[O-])cc2)C(c2ccc(F)cc2)C1COCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H](O[C@H]1OC[C@H](COC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](COCc2ccccc2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -25 °C

Procedure:
The intermediate from example 1 step G (10.95 g, 17.0 mmol) was combined with (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (4.39 g, 17.0 mmol) and dissolved in 170 mL DCM. The vessel was cooled to −25° C. followed by the addition boron trifluoride etherate (0.48 g, 3.4 mmol). The reaction vessel was maintained at −25° C. for 1 hr. The reaction was quenched by the addition of a saturated solution of NaHCO3 and the mixture was allowed to warm to ambient temperature. The aqueous mixture was extracted several times with EtOAc and washed with brine, dried over Na2SO4, filtered through a fritted funnel and concentrated in vacuo. The crude residue was purified on silica gel and eluted toluene. The first component collected off the column was the unwanted diastereomer. The second component collected was the desired diastereomer and was determined to be 85% pure as determined by 1HNMR. The product was recrystallized from cold methanol to provide the pure title compound. 1H-NMR (CDCl3): δ 1.41 (d, 3H, J=6.5 Hz), 1.76-1.84 (m, 1H), 2.50-2.62 (m, 1H), 3.02 (dd, 1H, J=9.0, 12.0 Hz), 3.07 (dd, 1H, J=3.0, 9.5 Hz), 3.41 (dd, 1H, J=2.5, 10.0 Hz), 3.54 (dd, 1H, J=11.5, 11.5 Hz), 4.26-4.36 (m, 5H), 4.56 (dd, 1H, J=3.5, 11.0 Hz), 4.99 (q, 1H, J=6.5 Hz), 6.92-7.06 (m, 4H), 7.20-7.36 (m, 7H), 7.71 (s, 1H), 8.19 (d, 2H, J=9.0 Hz), 8.31 (d, 2H, J=9.0 Hz) ppm.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:18])[CH2:15][O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC.[CH3:45][Si:46]([CH3:77])([C:71]([CH3:76])([CH3:75])[CH:72]([CH3:74])[CH3:73])[O:47][C:48]1[CH:55]=[C:54]([O:56][CH2:57][CH2:58][C:59]2[N:60]=[C:61]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[O:62][C:63]=2[CH3:64])[CH:53]=[CH:52][C:49]=1[CH:50]=[O:51]>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:18])[C@@H:15]([O:16][CH3:17])[C@@H:50]([C:49]1[CH:52]=[CH:53][C:54]([O:56][CH2:57][CH2:58][C:59]2[N:60]=[C:61]([C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)[O:62][C:63]=2[CH3:64])=[CH:55][C:48]=1[O:47][Si:46]([CH3:77])([CH3:45])[C:71]([CH3:76])([CH3:75])[CH:72]([CH3:74])[CH3:73])[OH:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c(O[Si](C)(C)C(C)(C)C(C)C)c1
Reactant: COCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1O[Si](C)(C)C(C)(C)C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1.8 g (7.21 mmol) (S)-4-Benzyl-3-methoxyacetyl-oxazolidin-2-one (for the preparation of (S)-4-benzyl-3-methoxyacetyl-oxazolidin-2-one see: D. Hunziker, N. Wu, K. Kenoshita, D. E. Cane, C. Khosla, Tetrahedron Lett. 1999, 40, 635-638) were dissolved under an argon atmosphere in 10 ml CH2Cl2 and treated with 1.44 ml (8.42 mmol) Hünig's base. After cooling to −78° C., nBu2BOTf was added slowly (7.21 ml of 1M solution in CH2Cl2) and enolborinate formation allowed to proceed for 0.25 hours at −78° C. and for 1 hour at 0° C. After recooling to −78° C., a solution of 2.8 g (6 mmol) of 2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde in 10 ml CH2Cl2 was added via dropping funnel during 90 minutes and the mixture kept for 95 minutes at −78° C. and for one hour at 0° C. Pouring onto crashed ice, twofold extraction with AcOEt, washing with brine and water, drying over magnesium sulfate, and evaporation of the solvents, followed by chromatography (silica gel, heptane/AcOEt) left finally 2.905 g (67%) of the title compound as a yellow oil. According to 1H-NMR spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry 1999, 10, 1353-1367.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1[CH:19]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21]1[C:25]([C:26](=[O:36])[CH2:27]P(=O)(OCC)OCC)=[CH:24][C:23]2[CH:37]=[CH:38][CH:39]=[CH:40][C:22]1=2>C(Cl)Cl.[Cl-].[Li+].C1COCC1>[C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:27]/[C:26]([C:25]1[S:21][C:22]2[CH:40]=[CH:39][CH:38]=[CH:37][C:23]=2[CH:24]=1)=[O:36])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: CCOP(=O)(CC(=O)c1cc2ccccc2s1)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1C[C@@H]2[C@@H](/C=C/C(=O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Temperature: -20 °C

Procedure:
A reactor equipped with a mechanical stirrer, under nitrogen, is charged with (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (99.2 g, 0.362 mol) in DCM and lithium chloride (1 molar equivalent) dissolved in THF. Diethyl 2-(benzo[b]thiophen-2-yl)-2-oxoethylphosphonate (1 molar equivalent) is added neat and rinsed with DCM. Some lithium chloride precipitates from solution when the THF and DCM solutions are mixed. The mixture is stirred under nitrogen and cooled to −20° C. After adding the phosphonate and subsequent stirring and cooling, the lithium chloride dissolved. After stirring for 2.5 hours, triethylamine (1 molar equivalent) is added neat via addition funnel and the temperature is held at −5° C. and stirred at this temperature for 19 hours. The temperature is adjusted to 0° C. and treated with 5% aqueous citric acid and the layers are separated. The organic layer is dried over magnesium sulfate and filtered. The crude product is purified on silica gel, eluted with ethyl acetate-hexanes (1:1) to afford the title intermediate 4a.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=O)=[CH:6][CH:5]=1)[CH3:2].[C:14]1([N:20]2[C:24]([NH2:25])=[CH:23][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:9]=[C:8]2[C:7]([N:10]=[C:23]3[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:21][N:20]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:24]3=[N:25]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: Nc1cc(-c2ccccc2)nn1-c1ccccc1
Reactant: CCN(CC)c1ccc(N=O)cc1
Solvent: CC(=O)O
Product: CCN(CC)c1ccc2nc3c(-c4ccccc4)nn(-c4ccccc4)c3nc2c1
Yield: 40.7 %

Procedure:
1.78 g N,N-diethyl-p-nitrosoaniline and 2.65 g 1,3-diphenyl-5-aminopyrazole were refluxed for 2 hrs in acetic acid. The mixture was concentrated to half volume. Water was added to get a precipitate, then filtered. The solid was purified by chromatograph column on silica gel. After removing the solvent, 1.6 g pure 7-diethylamino-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoxaline (DEDPPQ) was obtained as a brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=O)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22](=[O:33])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH2:24].O.CO>C1(OC)C=CC=CC=1.[Pd]>[CH3:20][O:21][C:22](=[O:33])[CH:23]([NH:24][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9](=[O:10])[C:8]1[CH:18]=[CH:19][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(C(=O)C2CCCCC2=O)cc1
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: COc1ccccc1
Product: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(C(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 41 %

Procedure:
To a mixture of 2-(4-tert-butylbenzoyl)cyclohexanone (116.1 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on carbon (20 g), then the mixture is heated to reflux for 2 h while the resulting water is removed by a Dean-Stark apparatus. The mixture is cooled to 80° C., and the Pd/C is filtered and washed with anisole (3×60 ml). The mixture is cooled to 40° C., hexane (1000 ml) is added and the mixture kept at −20° C. for 48 h. The solid is filtered and washed with hexane (5×200 ml) to yield the crude 2-[(2-(4-tert-butylbenzoyl)phenyl)-amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester. The crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2×50 ml), and dried under a vacuum to give the title compound (70.7 g, 41.0%).
Reaction SMILES: [CH3:1][Si:2]([CH3:25])([CH3:24])[O:3][Si:4]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.N1C=CC=CC=1.Cl[C:33]([O:35][CH:36]=[CH2:37])=[O:34]>CCOCC>[CH:36]([O:35][C:33]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][Si:4]([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[O:3][Si:2]([CH3:24])([CH3:1])[CH3:25])[CH2:9][CH2:10]1)=[O:34])=[CH2:37]
Reactant: C[Si](C)(C)O[Si](CCCN1CCNCC1)(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: C=COC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=COC(=O)N1CCN(CCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 68.6 %

Procedure:
To a 250 mL 3-neck round bottom flask fitted with a magnetic stirrer, condenser, nitrogen blanket, dropping funnel, thermometer and ice-water bath was added 5.0 g (11.8 mmol) of 3-tris(trimethylsiloxy)silylpropyl piperazine, 0.98 g (12.4 mmol) pyridine and 100 mL ether. To the reaction mixture was added 1.32 g (12.4 mmol) vinyl chloroformate so that the temperature remained below 15°. After stirring for 18 hours the reaction mixture was washed with 100 mL 2N HCl, 100 mL 2N NaOH and the organic phase was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting oil was chromatographed (silica gel, methylene chloride). The product was recovered as an oil 4.0 g (8.1 mmol, 68.8% yield). FTIR (neat, capillary) 2957.40, 2900.69, 2808.30, 2770.50, 1646.32, 1460.48, 1429.87, 1373.46, 1353.45, 1334.61, 1291.27, 1249.73, 1227.01, 1187.92, 1152.02, 1100.89, 1039.50, 1000.33, 952.03, 833.45, 752.98, 712.79, 686.52, 656.44. NMR (CDCl3) 6.89-7.30 (1H,dd), 4.28- 4.76 (2H,m), 3.30-3.60 (2H,m), 2.19-2.40 (2H,m), 1.21-1.63 (2H,m), 0.17-0.63 (2H,m), 0.00 (27H,s). ##STR37##
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]([CH2:11][C:12]#[N:13])[CH2:6][C:7](OC)=[O:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[OH:2][CH2:3][CH2:4][CH:5]([CH2:6][CH2:7][OH:8])[CH2:11][C:12]#[N:13]
Reactant: COC(=O)CC(CC#N)CC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(CCO)CCO
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Under nitrogen atmosphere, 3-cyanomethyl-pentanedioic acid dimethyl ester (212 g) was added to a suspension of LiAlH4 (50.0 g) in THF (1.8 L) at −20° C. After stirring for 30 min., H2O (200 mL) was slowly added to the reaction mixture. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure to obtain 5-hydroxy-3-(2-hydroxy-ethyl)-pentanenitrile (131 g). 1H NMR (200 MHz, CDCl3) δ ppm 1.38-1.91 (m, 4 H) 1.98-2.36 (m, 1 H) 2.50 (d, J=5.71 Hz, 2 H) 3.51-3.90 (m, 4 H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15]3[C:20]([C:21]=2I)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[CH2:30]([OH:34])[CH2:31][C:32]#[CH:33].O>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15]3[C:20]([C:21]=2[C:33]#[C:32][CH2:31][CH2:30][OH:34])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)c(I)c2ccccc21
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CCNCC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)c(C#CCCO)c2ccccc21
Temperature: 50 °C
Reaction time: 3.7 h
Yield: 86.6 %

Procedure:
3-Amino-6-[1-(tert-butoxycarbonyl)-3-iodoindol-2-yl]phtalimide (150 mg, 0.298 mmol) was dissolved in diethylamine (7.5 mL), and the solution was added with bis(triphenylphosphine)dichloropalladium (16.7 mg, 0.0234 mmol), copper iodide (11.4 mg, 0.0596 mmol) and 3-butyn-1-ol (0.226 mL, 2.98 mmol), followed by stirring at 50° C. for 3.7 hours under argon atmosphere. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 3-amino-6-[1-(tert-butoxycarbonyl)-3-(4-hydroxy-1-butynyl)indol-2-yl]phtalimide (115 mg, yield 87%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[F:26][C:27]1[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:29]3[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([F:26])[CH:28]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: COc1ccc([Mg]Br)cc1F
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1F

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 3-fluoro-4-methoxyphenylmagnesium bromide. Yield: 57 mg of a white solid. 1H NMR (400 MHz, CDCl3): δ 4.0 (s, 3H), 5.5 (s, 2H), 6.9-7.0 (m, 2H), 7.3-7.4 (m, 1H), 7.4-7.6 (m, 3H), 7.6-7.7 (m, 3H), 8.3 (s, 1H), 8.4-8.5 (m, 1H). LC-MSD, m/z for C23H16BrFN2O3 [M+H]+=467.0, 469.0; HPLC retention time: 2.3 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.[B:16](OC)([O:19]C)[O:17]C.Cl.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([B:16]([OH:19])[OH:17])[CH:3]=1
Reactant: COB(OC)OC
Reactant: CCc1ccc(Cl)cc1I
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1ccc(Cl)cc1B(O)O
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To a solution of 4-chloro-1-ethyl-2-iodo-benzene (5 g, 18.8 mmol) in anhydrous tetrahydrofuran (40 ml), cooled to −30° C., was added isopropyl magnesium chloride (2 M in tetrahydrofuran, 10 ml, 20 mmol) dropwise. After stirring at −30° C. for 30 minutes, trimethyl borate (4.2 ml, 38 mmol) was added dropwise and the mixture was stirred for 1.5 hours. The mixture was treated with hydrochloric acid (1 M, 25 ml), ethyl acetate (100 ml), and saturated aqueous sodium chloride solution (100 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was treated with hexane (50 ml) and the solid was filtered to afford 5-chloro-2-ethyl-phenyl boronic acid (1.8 g, 52% yield) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][OH:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][NH:28][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: NCCOCCO
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCO)ccc21
Yield: 71.2 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide (87 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-(2-aminoethoxy)-ethanol (30 mg), HBTU (116 mg), and DIEA (67 uL). LC/MS: m/z 480.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.48 (bs, 1H), 8.48 (t, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.78 (d, 1H), 7.69 (d, 1H), 7.51 (d, 1H), 7.36 (d, 1H), 3.68 (s, 3H), 3.57 (t, 2H), 3.52 (t, 2H), 3.49-3.41 (m, 4H), —OH proton signal was not observed.