Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([O:11][C:12](=[O:28])[CH2:13][NH:14][CH:15]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[CH2:17][CH2:16]1)([CH3:10])([CH3:9])[CH3:8].C([NH:39][C@H:40]([C:42](O)=[O:43])[CH3:41])(OCC1C=CC=CC=1)=O>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([O:11][C:12](=[O:28])[CH2:13][N:14]([C:42](=[O:43])[C@H:40]([CH3:41])[NH2:39])[CH:15]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[CH2:17][CH2:16]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1cc2c(cc1OC)C(NCC(=O)OC(C)(C)C)CC2
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(O)C(=O)O
Product: COc1cc2c(cc1OC)C(N(CC(=O)OC(C)(C)C)C(=O)[C@H](C)N)CC2
Yield: 48.5 %

Procedure:
By reacting 7 g of N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester oxalate with 4.8 g of N-carbobenzoxy-L-alanine and treating the reaction mixture as in Reference Example 5, there is obtained 4 g of L-alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester oxalate as colorless amorphous powder.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[C:12]#[N:13])=[CH:7][CH:6]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:6]1[CH:7]=[C:8]([CH:11]([CH3:14])[C:12]#[N:13])[CH:9]=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: COc1ccc(C(C)C#N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(C)C#N)cc1Br
Reaction time: 0.5 h

Procedure:
Bromine (21.4 ml) is added dropwise over a period of 1 hour to a stirred solution of 4-methoxyphenylpropionitrile (67.5 g) and sodium acetate (68.4 g) in glacial acetic acid (420 ml). The reaction mixture is stirred for an additional 30 minutes and partitioned between water and ether. The ether layer is washed with sodium carbonate solution, 10% aqueous NaOH, saturated salt, dried over Na2SO4 and filtered. The filtrate is evaporated in vacuo yielding the desired product, B.P. 155°-158° C. (4 mm).
Reaction SMILES: CC1(C)[O:19][CH:5]2[CH:6]3[CH2:11][O:10][CH:9]([OH:12])[CH:8]=[C:7]3[CH2:13][CH:14]([O:15][CH2:16][O:17][CH3:18])[CH:4]2[O:3]1.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CO>[CH3:18][O:17][CH2:16][O:15][CH:14]1[CH2:13][C:7]2=[CH:8][CH:9]([O:12][CH3:21])[O:10][CH2:11][CH:6]2[CH:5]([OH:19])[CH:4]1[OH:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COCOC1CC2=CC(O)OCC2C2OC(C)(C)OC12
Solvent: CCN(CC)CC
Solvent: CO
Product: COCOC1CC2=CC(OC)OCC2C(O)C1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
1,5,6,7,8,8a-Hexahydro-7,8-(dimethylmethylenedioxy)-6-methoxymethoxy-3H-2-benzopyran-3-ol (3.8 mg) was dissolved in 0.6 ml of dry methanol, and a catalytic amount of p-toluenesulfonic acid was added at room temperature. After the mixture was stirred at room temperature for 2 hours, triethylamine was added, and concentrated with water cooling under reduced pressure. The obtained residue was purified through a short silica gel column to provide 1.3 mg of 1,5,6,7,8,8a-hexahydro-6-methoxymethoxy-3-methoxy-3H-2-benzopyran-7,8-diol having the following properties (yield 68%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]=[CH2:31]>CC(C)=O>[CH2:31]([O:21][C:20](=[O:22])[C@@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:30]=[CH2:29]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 56 %

Procedure:
N-(t-Butoxycarbonyl)-D-tryptophan (3 g; 9.868 mmol) was dissolved in acetone and an aqueous solution of potassium carbonate (2.84 g; 20.58 mmol) added followed by allyl bromide (1.55 g; 12.81 mmol). The reaction mixture was stirred for 18 h and then the acetone was substantially removed by evaporation under reduced pressure. The oily water layer that remained was acidified to approximately pH=5 with 1N-hydrochloric acid and then extracted with methylene chloride. The methylene chloride layer was dried over anhydrous magnesium sulfate powder, filtered and evaporated under reduced pressure to give a foamy solid. The foam was further purified by column chromatography using silica gel and ethyl acetate and hexanes 2:1 v/v as eluant. In this manner, a 1.92 g yield (56%) of the desired product was obtained as an off white solid. FAB-MS:- calculated for C19H24N2O4 344; found 344 (M).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F-:13].[K+].CN(C)C=O>O>[F:13][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: [F-]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 160 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
93 g (0.5 mol) of 4-chloro-3-nitrobenzaldehyde and 58 g (1 mol) of potassium fluoride are suspended in 250 mol of dimethylformamide. The reaction mixture contains 0.02% of H2O. The mixture is stirred for one hour at 160° C. and the dimethylformamide is evaporated off in vacuo. The residue is cooled and stirred with 200 ml of water, the mixture is extracted with methylene chloride and the organic phase is dried. After the methylene chloride has been evaporated off, 83 g of 4-fluoro-3-nitrobenzaldehyde with a content of 90.2% are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Br:21][CH:22](Br)[CH3:23]>O>[Br:21][CH2:22][CH2:23][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCBr)cc1
Temperature: 30 °C
Reaction time: 0.75 h
Yield: 45.3 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (10.0 g, 82 mmol) and potassium carbonate (46 g, 326 mmol) was placed into 2 L round bottom flask, and DMF (150 mL) was added. The mixture was stirred for 45 min. and dibromoethane (46 g) was added in one portion, then the reaction mixture was allowed to stir at 25-35° C. for 96 hrs under a nitrogen atmosphere. The reaction mixture was cooled to 25-35° C. and then poured into water (500 mL). The mixture was extracted with EtOAc (3×100 mL), combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography over silicagel by using 10-15% ethyl acetate/pet. ether to afford the title compound (8.50 g, 45%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:3]=1.[C:14]([O:18][C:19](=[O:31])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[C:29]#[CH:30])([CH3:17])([CH3:16])[CH3:15].N1CCCCC1>CCOC(C)=O.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>[C:14]([O:18][C:19](=[O:31])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[C:29]#[C:30][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CCCS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1
Temperature: 70 °C

Procedure:
A mixture of 1-bromo-3-(propane-1-sulfonyl)-benzene (Intermediate 5; 493 mg, 1.87 mmol), tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3, 500 mg; 1.87 mmol), dichlorobis(triphenylphosphine)palladium(II) (52 mg; 0.07 mmol) and piperidine (550 μL; 5.6 mmol) was heated at 70° C. for 18 hours. The reaction mixture was taken up in EtOAc, washed twice with citric acid (0.5 M aqueous solution) and once with brine. The organic phase was dried over MgSO4, filtered and concentrated to dryness affording a crude, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as a dark orange sticky solid (640 mg, 76%).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])[CH:24]=[CH2:25])=[CH:18][C:17]=1[C:27]([F:30])([F:29])[F:28]>CN(C=O)C.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>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])/[CH:24]=[CH:25]/[C:2]2[CH:14]=[CH:13][C:5]([CH2:6][C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)=[CH:18][C:17]=1[C:27]([F:28])([F:29])[F:30]
Reactant: Ic1ccc(Cc2ccncc2)cc1
Reactant: C=CC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1ccc(Cc2ccncc2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 95 °C
Yield: 87.8 %

Procedure:
A mixture of 4-(4-iodobenzyl)pyridine (129 mg, 0.44 mmol), TEA (67 μL, 0.48 mmol), Pd(PPh3)4 (254 mg, 0.222 mmol) and N-[4-chloro-3-(trifluoromethyl)-phenyl]acrylamide (0.120 g, 0.44 mmol) in DMF (4.4 mL) was heated at 95° C. for 3 h. The reaction mixture was cooled to rt, diluted with water, extracted with EtOAc, washed with brine, dried over NaSO4, filtered and concentrated. The residue was purified by column chromatography to give the title compound (161 mg, 40%). LCMS: (FA) ES+ 417.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: Oc1ccc(F)cc1
Product: COc1ccc2c(Oc3ccc(F)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-fluoro-phenol to give [1-(4-fluoro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 351(MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH2:10])[CH2:4][CH2:3]1.[Br:11][C:12]1[CH:17]=[CH:16][C:15](I)=[C:14]([CH3:19])[CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[C:14]([CH3:19])[CH:13]=1
Reactant: Cc1cc(Br)ccc1I
Reactant: CC1CCN(CCN)CC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cc1cc(Br)ccc1NCCN1CCC(C)CC1

Procedure:
5.00 g (35.00 mmol) of 2-(4-methylpiperidin-1-yl)ethylamine was added under argon to a mixture of 10.39 g (35.00 mmol) of 4-bromo-1-iodo-2-methylbenzene, 0.33 g (1.75 mmol) of CuI, 30.0 g (141.00 mmol) of potassium phosphate, and 4.34 g (70.00 mmol) of ethylene glycol in 35 mL of isopropanol and the mixture was refluxed for 15 hours. The reaction mixture was evaporated down in vacuo and the residue taken up in EtOAc. The organic phase was washed with 5% aqueous ammonia, dried over magnesium sulfate, and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, EtOAc). Yield: 1.20 g (11% of theoretical); C15H23BrN2 (M=311.261); calc.: molpeak (M+H)+: 311/313 (Br); found: molpeak (M+H)+: 311/313 (Br); HPLC-MS: 4.24 minutes (method B).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[O:21]=[C:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH2:28][CH:29]=O>>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH2:29][CH2:28][CH2:27][N:23]3[CH2:24][CH2:25][CH2:26][C:22]3=[O:21])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: O=CCCN1CCCC1=O
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCN1CCCC1=O

Procedure:
This compound was prepared from ethyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate and 3-(2-oxo-1-pyrrolidinyl)propanal employing methods similar to those described in Example 265 and was obtained as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=1.6 Hz, 1 H), 7.71 (br, 1 H), 7.07 (dd, J=8.5, 5.4 Hz, 2 H), 6.92 (t, J=8.6 Hz, 2 H), 6.74 (d, J=1.3 Hz, 1 H), 4.35 (q, J=7.1 Hz, 2 H), 3.86 (s, 2 H), 3.35-3.29 (m, 4 H), 3.10 (m, 2 H), 2.33 (t, J=8.2 Hz, 2 H), 1.96 (m, 2 H), 1.79 (m, 2 H), 1.35 (t, J=7.2 Hz, 3 H); MS m/z 400 (M+H)+.
Reaction SMILES: Br.[CH3:2][N:3]1[C@@H:19]2[CH2:20][C:8]3[CH:9]=[CH:10][C:11]([O:23][CH3:24])=[C:12]4[O:13][C@H:14]5[C:15]([O:21]C)=[CH:16][CH:17]=[C:18]2[C@:6]5([C:7]=34)[CH2:5][CH2:4]1.C(=O)=O>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:2][N:3]1[C@@H:19]2[CH2:20][C:8]3[CH:9]=[CH:10][C:11]([O:23][CH3:24])=[C:12]4[O:13][C@H:14]5[C:15]([CH:16]=[CH:17][C@@H:18]2[C@:6]5([C:7]=34)[CH2:5][CH2:4]1)=[O:21]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: Br
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314

Procedure:
Anhydrous hydrogen bromide in glacial acetic acid (6 ml of 45% w/v solution) was added dropwise with stirring to a cooled (-15° C.) solution of thebaine (2 g) in chloroform (6 ml) over a period of 9 minutes. When the addition was complete the Drikold bath was removed and the temperature allowed to rise.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26](C)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:30])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N
Reactant: CC(C)CCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Product: CC(C)CCc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 378) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (0.090g 21%). mp 180-183° C. 1H NMR (300 MHz, DMSO d6) δ 0.78 (d, J=6 Hz, 6H), 1.49 (m, 5H), 7.36 (m, 2H), 7.53 (m, 2H), 7.62-7.73 (m, 4H), 7.98 (m, 3H). MS (DCI/NH3) m/z 416 (M+H)+, 433 (M+NH4)+. Anal. calc. for C21H22FN3O3S: C, 60.71; H, 5.34; N, 10.11. Found: C, 60.37, H, 5.36, N, 9.84.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].N1C=CC=CC=1>>[C:10]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: OCC1CCC(O)CC1
Solvent: c1ccncc1
Product: CC(=O)OCC1CCC(O)CC1

Procedure:
The 4-(hydroxymethyl)cylohexan-1-ol obtained above is treated with 1 eq. of acetic anhydride and 2 eq. of pyridine to provide 4-acetoxymethylcylohexan-1-ol.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:4].[NH2:19][CH:20]1[C:28]2[C:23](=[CH:24][C:25]([CH2:29][C:30]3[CH:31]=[C:32]([CH2:40][OH:41])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:18])([F:17])[C:3]([NH:19][CH:20]1[C:28]2[C:23](=[CH:24][C:25]([CH2:29][C:30]3[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[C:32]([CH2:40][OH:41])[CH:31]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:4]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: NC1CCc2cc(Cc3cc(CO)cc(C(F)(F)F)c3)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCc2cc(Cc3cc(CO)cc(C(F)(F)F)c3)ccc21)C(F)(F)F
Yield: 26.5 %

Procedure:
Pentafluorophenyl trifluoroacetate (28 mg, 0.1 mmol) was added to a solution of (3-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)phenyl)methanol (30 mg, 0.093 mmol) and triethylamine (26 μL, 0.187) in DCM (1 mL). The reaction was stirred at rt for 24 h before aq. sat. NaHCO3 (2 mL) was added to the mixture and the whole was filtered over a phase separator. The organic filtrate was evaporated to dryness in a Genevac. The crude material was purified by prep. LCMS to afford LEBE27-031-2 the title compound (10.3 mg, 27.7%). MS (ESI): m/z [M−H]− 416.0
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[C:17]4[CH2:18][CH2:19][CH:20]([C:22](O)=[O:23])[CH2:21][C:16]=4[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:25]([NH2:28])[CH:26]=[CH2:27]>C1COCC1>[CH2:25]([NH:28][C:22]([CH:20]1[CH2:19][CH2:18][C:17]2[C:10]3[C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:15][C:16]=2[CH2:21]1)=[O:23])[CH:26]=[CH2:27]
Reactant: O=C(O)C1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Reactant: C=CCN
Solvent: C1CCOC1
Product: C=CCNC(=O)C1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 15 mL round-bottom flask were added 50 mg (0.124 mmol, 1 equiv) of 4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid, 1, 20 mg (0.124 mmol, 1 equiv) of CDl and THF (1.25 mL). The reaction was stirred for 4 h at rt and then 0.01 mL (0.186 mmol, 1.5 equiv) of allyl amine was added via syringe and the reaction was allowed to stir at rt overnight. The reaction was stopped and THF was concentrated in vacuo and the crude solid was re-dissolved in CH2Cl2 (5 mL). This solution was poured into a separatory funnel and washed with satd NaHCO3 (1×5 mL), water (1×5 mL), and brine (1×5 mL). The organic layer was dried (MgSO4), filtered and concentrated to yield a white solid. The compound was triturated with diethyl ether to yield pure material, 56, as a white solid (36 mg, 66%). 1H-NMR (DMSO-d6) δ 8.42 (s, 1H), 8.31 (s, 1H), 8.19 (t, 1H), 7.86 (m, 1H), 7.63 (m, 1H), 7.25 (m, 2H), 5.82 (m, 1H), 5.08 (m, 2H), 3.75 (t, 2H), 3.21 (m, 2H), 2.97 (d, 2H), 2.69 (m, 1H), 2.15 (m, 1H), 1.82 (m, 1H); LCMS RT=2.78 min; [M+H]+=444.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:37])[C:33]([OH:36])([CH3:35])[CH3:34])[NH:27][C:26](=[O:38])[CH2:25]2>>[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:37])[C:33]([OH:36])([CH3:35])[CH3:34])[NH:27][C:26](=[O:38])[C:25]2=[CH:19][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]=2[C:2]=1[CH3:1]
Reactant: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)C(C)(C)O)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 43 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide as starting materials to give N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-2-methyl-propionamide (40 mg, 43%) as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:6]3[C:12](I)=[N:11][N:10]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:43]([Si:45]([CH3:48])([CH3:47])[CH3:46])#[CH:44]>C1COCC1.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>[CH:1]1([C:4]2[C:5]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:6]3[C:12]([C:44]#[C:43][Si:45]([CH3:48])([CH3:47])[CH3:46])=[N:11][N:10]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C#C[Si](C)(C)C)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
tert-Butyl 4-(5-cyclopropyl-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (300 mg, 0.5 mmol), Cu(I)I (5 mg, 0.02 mmol), PdCl2(PPh3)2 (18 mg, 0.02 mmol), and triethylamine (0.3 mL, 2.5 mmol) were placed in THF (4 mL) and de-gassed under argon. Ethynyltrimethylsilane (0.2 mL, 1.5 mmol) was then added, and the reaction was stirred at room temperature overnight. The reaction was then concentrated to dryness to give the crude product tert-butyl 4-(5-cyclopropyl-1-(4-methoxybenzyl)-3-((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (280 mg, 98% yield).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34]([C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35].N1CCOCC1.C(O)C(N)(CO)CO>C(Cl)Cl>[C:34]([C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)[CH2:17][C:16]2[CH:15]=[CH:14][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=3)=[CH:33][CH:32]=2)=[O:46])=[CH:40][CH:39]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: C1COCCN1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)Nc3ccc(C(C)(C)C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}acetate (45 mg, 0.10 mmol) and 4-tert-butylphenylisocyanate (Aldrich, 27 mg, 0.15 mmol) in DCM (2 mL) was stirred at rt overnight in presence of a morpholine resin (1.5 eq., Novabiochem HL, 3.8 mmol/g). Trisamine resin (1.2 eq, Novabiochem, 3.5 mmol/g) was then added and the mixture was stirred at rt for an additional 2 hrs. The reaction mixture was then filtrated and the solvent was removed under reduced pressure to give quantitatively the title compound. HPLC, Rt: 5.97 min purity: 96.3%). M+(ESI): 619.6, M−(ESI): 616.9.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][CH:5]=1)([O-:3])=[O:2].[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5]2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1ccn(-c2ccc(F)cc2)c1
Yield: 35.7 %

Procedure:
To a dichloromethane solution (4.0 mL) of 3-nitropyrrole (200 mg, 1.78 mmol), 4-fluorophenylboronic acid (499 mg, 3.57 mmol), and copper acetate (II) (486 mg, 2.68 mmol), N,N-diisopropylethylamine (606 μL, 3.57 mmol) was added and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was filtered with Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (131 mg, yield 36%).