Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[NH2:38])=[CH:31][CH:30]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[C:22]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([N:35]2[C:36](=[O:41])[C:37]([CH3:39])([CH3:40])[NH:38][C:9]2=[O:11])=[CH:31][CH:30]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(C)c1Oc1ccc(NC(=O)C(C)(C)N)cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C)c1Oc1ccc(N2C(=O)NC(C)(C)C2=O)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 189.1 %

Procedure:
In a 50 mL round-bottomed flask N-{6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}-2-methylalaninamide (Intermediate 80, 144.4 mg) was dissolved in dichloromethane (5 mL) to give a pale yellow solution. The reaction mixture was cooled at 0° C. N,N-dimethyl-4-pyridinamine (27.7 mg, 0.227 mmol), triethylamine (0.158 mL, 1.134 mmol) and triphosgene (67.3 mg, 0.227 mmol) were added. The reaction mixture was stirred at 0° C. After 20 min, the solvent was evaporated under vacuum to afford a yellow solid which was purified via silica gel chromatography (Biotage system, 10 g SNAP column) using as eluent a gradient Cyclohexane/EtOAc from 2:1 to 1:3 in 20 CV; then 1:3 for 5 CV. The collected fractions afforded the title compound as a white solid (139.7 mg).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:23][C:24]1[CH2:28][CH:27]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][O:38][Si](C(C)C)(C(C)C)C(C)C)[CH:31]=2)[C:26](=[O:49])[CH:25]=1)[CH:20]([CH3:22])[CH3:21]>O1CCCC1>[OH:38][CH2:37][CH2:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][CH:27]1[C:26](=[O:49])[CH:25]=[C:24]([O:23][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:28]1
Reactant: CC(C)COC1=CC(=O)C(Cc2cccc(CCO[Si](C(C)C)(C(C)C)C(C)C)c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)COC1=CC(=O)C(Cc2cccc(CCO)c2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A solution of tetrabutylammonium fluoride (1 M in tetrahydrofuran, 0.47 mL, 0.47 mmol) was added dropwise to an ice-water bath cooled solution of 20 (0.071 g, 0.16 mmol) in anhydrous tetrahydrofuran (1 mL). The reaction mixture was stirred at 0° C. for 3 h and then quenched with a saturated solution of ammonium chloride. The two phases were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography using dichloromethane-methanol 95:5 as eluent to provide the desired product as colorless oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.O.CN(C)[CH:32]=[O:33]>>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:32]([OH:33])=[N:21][N:20]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CSc1ccc(-c2coc3ccc(C(=O)NN)cc23)cc1
Reactant: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1ccc(-c2coc3ccc(-c4nnc(O)o4)cc23)cc1
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 3-[4-(methylthio)phenyl]-1-benzofuran-5-carbohydrazide (0.25 g, 0.83 mmol) and triethylamine (0.17 mL, 1.25 mmol) in N,N-dimethylformamide (5 mL) was added N,N′-carbonyldiimidazole (0.27 g, 1.68 mmol) at 0° C., and the resulting mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (0.20 g, yield 74%) as colorless crystals.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[CH2:6][CH2:7][CH3:8].[N+]([O-])(O)=O.S(=O)(=O)(O)O>S(=O)(=O)(O)O>[N+:1]([C:12]1[CH:11]=[C:10]([C:5](=[O:9])[CH2:6][CH2:7][CH3:8])[CH:15]=[CH:14][CH:13]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCCC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: CCCC(=O)c1cccc([N+](=O)[O-])c1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
Concentrated nitric acid (40 ml) was added cautiously with cooling to concentrated sulphuric acid (100 ml) maintaining a temperature of −5° C. Another solution of butyrophenone (59.2 g, 0.47 mol) in concentrated sulphuric acid (140 ml) was made up with shaking, keeping the temperature at −5° C. (+/−5° C.). The former nitric acid/sulphuric acid solution was added portionwise over 45 min to the latter solution of ketone in sulphuric acid keeping the temperature at −10° C.+/−5° C. during the addition and for a subsequent 30 min. The reaction mixture was poured onto crushed ice (1.5 1) and then extracted with diethyl ether (200 ml and then 3×100 ml). The combined organic extracts were washed with water and then aqueous saturated sodium hydrogen carbonate solution and dried (MgSO4) before concentrating in vacuo. The crude yellow oil crystallised after 16 h and was then purified by chromatography on silica gel (1 kg) eluting with hexane:diethyl ether (9:1) to give the title compound as a white solid (9.1 g, 10%).
Reaction SMILES: COC1C=CC(COC([NH:11][CH:12]2[CH2:17][CH:16]=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13]2)=O)=CC=1.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>C1(OC)C=CC=CC=1>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[NH2:11][CH:12]1[CH2:17][CH:16]=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13]1
Reactant: COC(=O)C1=CC(NC(=O)OCc2ccc(OC)cc2)CC=C1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1=CC(N)CC=C1
Temperature: 0 °C

Procedure:
To a suspension of 16.5 g of methyl 3-(p-methoxybenzyloxycarbonylamino)-1,5-cyclohexadienecarboxylate in 40 ml of anisole at about 25° C. is added slowly 30 ml of trifluoroacetic acid. After the addition of the first 5 ml the solid dissolves. The solution is cooled in a ice bath and the addition of trifluoroacetic acid continues. The solution is maintained at 0° C. for one hour, then the solvents are removed in vacuo (1 mm) maintaining the temperature below 40° C. The resulting oily residue is cooled to 0° C. and anhydrous ether added with stirring. The precipitate is filtered off to give 8.1 g of methyl 3-amino-1,5-cyclohexadienecarboxylate trifluoroacetate.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([Cl:20])=[C:18](I)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1.C([Mg]Cl)(C)C.CO[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1.[NH4+].[Cl-]>>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([Cl:20])=[C:18]([B:34]3[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]3)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2ncc(I)c2Cl)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2Cl)OC1(C)C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-chloro-4-iodo-1H-pyrazole (30.0 mg, 0.0680 mmol) in THF (1 mL, 20 mmol) at rt was added 2 M isopropylmagnesium chloride in THF (0.10 mL, 0.20 mmol), and the mixture was stirred for 20 min. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.045 mL, 0.27 mmol), and allowed to stir at rt for 1 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was concentrated in vacuo to afford the title compound as a white solid. The material was used in the next step without further purification. 1H NMR (400 MHz, CD3OD): δ=0.12 (s, 6H), 0.93 (s, 9H), 1.33 (s, 8H), 1.46-1.60 (m, 2H), 1.86-2.09 (m, 6H), 3.70-3.82 (m, 1H), 4.38 (ddd, J=10.5, 5.2, 5.1 Hz, 1H), 7.69 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[C:7]([CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH2:10]1)=[O:8].[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:23][C:24]2[CH:31]=[CH:30][CH:29]=[C:26]([CH3:27])[CH:25]=2)[CH:10]=1)=[O:8]
Reactant: Cc1cccc(CBr)c1
Reactant: Cc1cccc(C(=O)C2CNc3ccccc3C2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3cccc(C)c3)c(=O)c3ccccc32)c1
Yield: 50.1 %

Procedure:
Compound 4y was prepared following the procedure outlined in Step 3 of Example 1 using 26 mg (0.65 mmol) of sodium hydride (60%), 132 mg (0.50 mmol) of 3-(3-methyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one, 3 mL of anhydrous dimethylformamide, and 120 mg (0.65 mmol) of 3-methylbenzylbromide. The crude product was purified by flash chromatography to yield 92 mg of a colorless solid 4y: LC-MSD, m/z for C25H21NO2, [M+H]+=368.5, [M+2H]+=369.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.586 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.37 (s, 3H), 2.42 (s, 3H), 5.39 (s, 2H), 7.01 (d, 2H), 7.15 (d, 1H), 7.22-7.44 (m, 5H), 7.55-7.58 (m, 3H), 8.29 (s, 1H), 8.47 (d, 1H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14](C)[CH2:15]C(O)=O)=[CH:10][CH:9]=1>ClCCl>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[CH2:1][C:2]([Cl:4])=[O:3])=[CH:10][CH:9]=1
Reactant: CC(CC(=O)O)c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(CC(=O)Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.6 %

Procedure:
Oxalyl chloride (71 g, 48.8 ml, 0.560 mol, Aldrich) was added to a mixture of 3-(4-fluorophenyl)butyric acid (34 g, 0.187 mol) in 200 ml of dichloromethane at -5° C. After stirring for 20 min at this temperature, the solution was allowed to warm to 25° C. and stirring was continued for 2 h. The volatiles were removed by spin evaporation in vacuo with the addition of dichloromethane (4 ×) during concentration to give 35.1 g (94%) of 3-(4-fluorophenyl)butyryl chloride as a light yellow oil;
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[C:14]([O:18][C:19]([N:21]1[CH2:26][C@@H:25]([CH3:27])[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][C@@H:22]1[CH:35]=[O:36])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][C@@H:25]([CH3:27])[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][C@@H:22]1[CH:35]([OH:36])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C=O)CN1C(=O)OC(C)(C)C
Reactant: Brc1nccs1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C(O)c2nccs2)CN1C(=O)OC(C)(C)C
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
2-Bromothiazole (0.500 g, 3.05 mmol) was dissolved in anhydrous THF (7.62 mL) and cooled to 4° C. (ice bath) under nitrogen. i-PrMgCl.LiCl in THF (2.0 M, 1.52 mL, 3.05 mmol) was added and the reaction stirred at this temperature for 30 minutes. The ice bath was removed and the reaction stirred for 30 minutes at room temperature. (2R,5R)-2-Formyl-5-methyl-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.500 g, 1.52 mmol) was added and the reaction stirred for 2 h. The reaction mixture was quenched with water and extracted with DCM (3×). The combined organic extracts were dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60) gave the title compound (473 mg). MS: [M+H]+=414.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([NH:41][CH2:42][C:43](O)=[O:44])(OC(C)(C)C)=O>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:43](=[O:44])[CH2:42][NH2:41])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: NCC(=O)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and Boc-glycine (21.0 mg) were reacted and treated in the same manner as in the method described in Example 29 to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.[C:12]1(C=CCO)C=CC=CC=1.N>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][C@H:9]2[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: OCC=Cc1ccccc1
Reactant: OC/C=C/c1ccc(Br)cc1
Agent: N
Product: OC[C@@H]1C[C@H]1c1ccc(Br)cc1

Procedure:
The title compound was prepared by the method of A. B. Charette and H. Lebel (Organic Synthesis, 1998, 76, 86-96) substituting trans-3-(4-Bromophenyl)prop-2-en-1-ol (the product from Example 1A) for 3-Phenyl-prop-2-en-1-ol. 1H NMR (300 MHz, CDCl3): δ 0.92-1.0 (m, 2H), 1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H), 3.61 (d, J=7.5 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 228 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)=[CH:5][CH:4]=1)=[O:2].[CH3:29][Mg]Br>C(OCC)(=O)C.CCCCCC>[OH:2][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)=[CH:5][CH:4]=1)[CH3:29]
Reactant: C[Mg]Br
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C=O)cc1)CO2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)O)cc1)CO2
Yield: 93 %

Procedure:
Using N-(3-(4-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide and methylmagnesium bromide, the title compound was synthesized in the same manner as Example 22. Yield: 93%. Melting point: 144-145° C. (ethyl acetate-hexane).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.[NH2:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.CCOC(C)=O>[NH2:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)[CH:25]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cc(N)ncn3)cc(C)c21
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To the mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.04 g, 4 mmol) and 4-amino-6-chloropyrimidine (520 mg, 4 mmol) in CH3CN (20 ml), added Cs2CO3 (3.9 g, 12 mmol). The mixture was stirred at 50° C. for 24 hours. The result mixture was diluted with EtOAc (200 ml), washed with water and brine, dried over Na2SO4. Concentrated to give light yellow oil used for next step without further purification. MS (ESI negative): (M−H)−=342.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)[CH:3]=1.N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].O>CN(C)C=O>[Si:27]([O:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([CH3:8])[N:5]=2)[CH2:10][CH2:11]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28]
Reactant: Cc1nc(Cl)cc(N2CCN(CCO)CC2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(Cl)cc(N2CCN(CCO[Si](C)(C)C(C)(C)C)CC2)n1
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of 2-(4-(6-chloro-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol obtained in Step A (1.00 g) and imidazole (0.636 g) in N,N-dimethylformamide (13 mL) was added tert-butyl(chloro)dimethylsilane (0.793 g) at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.42 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[F:21][CH:22]([F:47])[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH3:33])[N:28]=[C:27]2[Sn](CCCC)(CCCC)CCCC>CN(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.[Cu]I>[F:47][CH:22]([F:21])[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH3:33])[N:28]=[C:27]2[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(OC(F)F)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 72.8 %

Procedure:
2-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (224 mg, 629 μmol) and 5-(difluoromethoxy)-1-methyl-3-(tributylstannyl)-1H-indazole (398 mg, 818 μmol.30) were dissolved in DMF (3 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (36.3 mg, 31.4 μmol) and CuI (24.0 mg, 126 μmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 2.5 h. The reaction mixture was concentrated under high vacuum and the residue was purified by chromatography (80 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 30 min) to give 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (217 mg, 458 μmol, 72.9%) as a light brown solid. MS (M+H)+=474; 1H NMR (CDCl3) δ: 10.51 (br. s., 1H), 9.29 (s, 1H), 8.61 (s, 1H), 8.30 (s, 1H), 7.38-7.52 (m, 1H), 7.27-7.36 (m, 1H), 6.69 (t, J=74.8 Hz, 1H), 5.76 (s, 2H), 4.20 (s, 3H), 3.56-3.70 (m, 2H), 0.91-1.02 (m, 2H), −0.08-0.06 (m, 9H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[CH2:33]O)[O:29][CH2:28][CH:27]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:26]2.O>C(#N)C>[Br:20][CH2:33][C:32]1[CH:31]=[C:30]2[C:25]([CH2:26][CH:27]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:28][O:29]2)=[CH:24][C:23]=1[F:22]
Reactant: CCCCCC1COc2cc(CO)c(F)cc2C1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CCCCCC1COc2cc(CBr)c(F)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.2 g (38.9 mmol) of triphenylphosphine are suspended in 80 ml of acetonitrile, and 2.0 ml (39.0 mmol) of bromine are added dropwise with ice cooling. A solution of 10.0 g (38.4 mmol) of (6-fluoro-3-pentylchroman-7-yl)methanol in 20 ml of acetonitrile is subsequently added, and the mixture is stirred overnight at room temp. After addition of water, the mixture is extracted three times with n-heptane, and the combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with heptane/toluene (4:1), giving 7-bromomethyl-6-fluoro-3-pentylchroman as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:32])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24]C(=O)OC(C)(C)C)=[O:16])=[CH:4][CH:3]=1>CCOC(C)=O>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)Nc1ccc(O)cc1
Solvent: CCOC(C)=O
Product: Nc1ccccc1NC(=O)CCCCCC(=O)Nc1ccc(O)cc1

Procedure:
The solution of tert-Butyl (2-(7-((4-hydroxyphenyl)amino)-7-oxoheptanamido)phenyl)carbamate in EtOAc was stirred at 0° C. and bubbled with the gas of HCl for 20 min. The pH value of the solution was adjusted to 6 by saturated aqueous solution of Na2CO3. The aqueous phase was extracted with EtOAc (100 mL). The organic layers were combined and dried over Na2SO4 and then concentrated to give the crude product. The crude product was purified by flash chromatography SiO2 (EtOAc) to give desired compound CC No. 3 (0.18 g, yield 18.5%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:30]2([CH3:31])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:32])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([OH:25])([CH2:23][CH3:24])[CH3:22])[CH2:12][C@@H:11]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br/[CH:42]=[CH:43]\[CH2:44][C:45]([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])([CH3:47])[CH3:46].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:30]2([CH3:31])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:32])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:25]/[CH:42]=[CH:43]\[CH2:44][C:45]([O:48][Si:49]([CH2:50][CH3:51])([CH2:52][CH3:53])[CH2:54][CH3:55])([CH3:46])[CH3:47])([CH2:23][CH3:24])[CH3:22])[CH2:12][C@@H:11]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:35])[CH3:36])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Si](CC)(CC)OC(C)(C)C/C=C\Br
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(O/C=C\CC(C)(C)O[Si](CC)(CC)CC)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 98 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-ethylpregna-5,7,16-triene (103 mg, 0.180 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-(2Z)-pentene (211 mg, 0.719 mol), sodium hydride (60% in oil, 43 mg, 1.08 mmol), 15-crown-5 (40 mg, 0.182 mmol) and tetrahydrofuran (3 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (reflux under heating for 1 hour), worked up and purified by column chromatography (hexane:toluene=1:1) to give the titled compound (141 mg, 100%) as a colorless solid.