Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[O:26][CH:27]([CH3:29])[CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:27]([O:26][C:20]1[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[CH:12]=2)[CH2:7]1)=[O:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2ccc(OC)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CC(NC(=O)c1cccc(C)c1OC(C)C)(C(=O)O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.3 %

Procedure:
The mixture of 2-(2-isopropoxy-3-methyl-benzoylamino)-5-methoxy-indan-2-carboxylic acid ethyl ester (92) (410 mg, 1 mmol) and KOH (1 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (93) as white solid (400 mg, 100%).
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[CH2:21])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]2[CH2:21][O:9]2)=[CH:15][CH:14]=1
Reactant: C=CCc1ccc(F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Fc1ccc(CC2CO2)cc1
Reaction time: 8 h
Yield: 98 %

Procedure:
To a stirred mixture of 86 parts of 3-chlorobenzeneperoxoic acid and 650 parts of dichloromethane are added dropwise (slowly) 53 parts of 1-fluoro-4-(2-propenyl)benzene. Upon completion, stirring is continued overnight at room temperature. Then there are added dropwise 92 parts of a potassium carbonate solution and the layers are separated. The organic phase is washed with a sodium bisulfite solution, dried, filtered and evaporated, yielding 58.4 parts (98%) of 2-(4-fluorophenylmethyl)oxirane as an oily residue.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:26])[C@:10]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])([OH:17])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@:10]([OH:17])([C@@H:9]([OH:8])[CH3:26])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 3.5 h
Yield: 868.9 %

Procedure:
To a solution of 0.10 g of (2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol in 1 mL of THF was added 0.3 mL of TBAF (1 M) at room temperature. Stirring was performed at room temperature for 3.5 hours, and 5 mL of water was added thereto. Then, extraction was performed with ethyl acetate (30 mL). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. The resulting product was purified by column on silica gel to obtain 0.61 g of the title compound (yield: 87%). 1H-NMR (400 MHz, CDCl3) δ: 0.97 (d, 3H, J=6.3 Hz), 4.31 (q, 1H, J=6.3 Hz), 4.79-4.82 (m, 2H), 6.67-6.81 (m, 2H), 7.32-7.38 (m, 1H), 7.72 (s, 1H), 7.93 (s, 1H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.Cl>CN(C)C=O>[CH2:1]([NH:3][CH2:4][CH2:5][O:6][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCNCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNCCOc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
2-(Ethylamino)-ethanol (2.5 g, 24.2 mmol) (Aldrich) was added to a cooled (−5° C.) mixture of sodium hydride (50%, 580 mg, 24.2 mmol) in dimethyl-formamide (100 mL) and stirred for 10 minutes at 0° C., 30 minutes at room temperature, then 30 minutes at 45° C. After cooling to −1° C., 1-fluoro-4-nitrobenzene (4.1 g, 29 mmol) (Aldrich) was added and the mixture was stirred 20 minutes at −100° C. and for 90 minutes at room temperature. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid and the mixture extracted with ether (4×50 mL). The aqueous layer was adjusted to pH 9 with 3N sodium hydroxide and extracted with ethyl acetate (5×50 mL), dried (Na2SO4), concentrated in vacuo, and dried under high vacuum at 40° C. to give 2.2 g (41%) ethyl-[2-(4-nitro-phenoxy)-ethyl]-amine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12](=[O:13])[CH:11]=[CH:10]O[C:8]=1[CH3:14].[NH3:15]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:15]=[C:8]1[CH3:14]
Reactant: COCCCOc1c(C)occc1=O
Reactant: N
Product: COCCCOC1C(=O)C=CN=C1C
Yield: 100 %

Procedure:
A solution of 3-(3-methoxy-1-propoxy)-2-methyl-4-pyrone (0.31 g, 1.7 mmol) in 50 ml concentrated aqueous NH3 was heated to 120° C. for 2 h in an autoclave. The reaction mixture was transferred to a round bottomed flask and evaporation off the solvent afforded 0.32 g (100%) product as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([CH2:25][CH2:26][CH2:27][C:28]([O-:30])=[O:29])=[N:3]1.[K+].S(=O)(=O)(O)O.[CH2:37](O)[CH3:38]>>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:13]=2)=[N:5][C:4]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:37][CH3:38])=[O:29])=[N:3]1
Reactant: Cn1nc(CCCC(=O)[O-])nc1NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)CCCc1nc(NCCCOc2cccc(CN3CCCCC3)c2)n(C)n1

Procedure:
Potassium 1-methyl-5[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-butanoate (2.0 g) and concentrated sulphuric acid (1 ml) in anhydrous ethanol (200 ml) was heated under reflux for 16 h. The suspension was filtered, the filtrate evaporated, and saturated aqueous sodium bicarbonate (50 ml) added. The mixture was extracted with ethyl acetate, the extract washed with brine, dried, and evaporated to give the title compound (1.0 g) as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:29])[CH:8]=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:28])[CH:16]=[C:17]([NH:19][C:20]([C:22]3[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=3)=[O:21])[CH:18]=2)=[O:13])[N:10]=1)=[O:5])C.[OH-].[Na+:31].Cl.C(O)(C)C>CO>[CH3:29][N:7]1[CH:8]=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:28])[CH:16]=[C:17]([NH:19][C:20]([C:22]3[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=3)=[O:21])[CH:18]=2)=[O:13])[N:10]=[C:6]1[C:4]([O-:5])=[O:3].[Na+:31]
Reactant: CCOC(=O)c1nc(NC(=O)c2cc(NC(=O)c3nccn3C)cn2C)cn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Product: Cn1cc(NC(=O)c2nccn2C)cc1C(=O)Nc1cn(C)c(C(=O)[O-])n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
The compound 9 (3.0 g, 7.5 mmol) was dissolved in methanol (37.6 ml), mixed with aqueous solution of sodium hydroxide (37.6 ml, 7.89 mmol) and stirred for one hour at 50° C. After being cooled to a room temperature, the resulting solution was mixed with hydrochloric acid (1N) to reach pH 2.0, and then mixed with isopropylalcohol to give the white powder, which was then filtered to give the compound 10 (2.85 g, 94%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH2:30][CH3:31]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:29][CH2:30][CH3:31])[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CCCBr
Reactant: CCOc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2cccc3c2CCC3=O)ccc(OCC)c1OC
Temperature: 80 °C
Yield: 7.7 %

Procedure:
To a stirring solution of 4-(4-ethoxy-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.268 mmol) in acetonitrile was added potassium carbonate (111 mg, 0.805 mmol) and propyl bromide (99 mg, 0.805 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded title compound as a solid (7 mg, 7.7%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH:9]([NH:13][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[C:19]4[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[O:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1COCO[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[CH3:32][N:11]1[CH2:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)=[O:15])[CH2:10]1
Reactant: O=C(NC1CNCC(c2ccccc2)C1)c1ccc2[nH]nc(-c3ccncc3)c2c1
Reactant: C1OCOCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CC(NC(=O)c2ccc3[nH]nc(-c4ccncc4)c3c2)CC(c2ccccc2)C1
Reaction time: 1 h

Procedure:
In a flask, dichloromethane (1 mL) and acetic acid (1 drop) was added to N-(5-phenylpiperidin-3-yl)-3-(pyridin-4-yl)-1H-indazole-5-carboxamide (0.05 mmol) and 1,3,5-trioxane (0.2 mmol). The reaction was stirred for 60 minutes. Sodium triacetoxyborohydride (1 mmol) was added in one portion. The reaction was stirred for 1 h. The reaction was concentrated in vacuo and purified using prep LC/MS.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](OC)=[O:27])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CN(Cc2ccccc2)c2cccc([N+](=O)[O-])c2C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(CO)cc2)cccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
The product from Example 6B (0.55 g, 1.4 mmoles) in THF (3.5 mL) was treated with diisobutylaluminum hydride (DIBAL) (2.94 mL, 2.94 mmoles, 1.0M in hexanes) dropwise at −78° C. After 30 minutes, an additional portion of DIBAL (1.5 mL) was added dropwise. After an additional 30 minutes, the acetone/dry ice bath was removed and the reaction mixture was carefully quenched with saturated NH4Cl. The mixture was diluted with diethyl ether (200 mL) and saturated sodium potassium tartrate (250 mL) and stirred vigorously for 2.5 hours. The two phases were separated and the organic phase was washed with brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 4:1→1:1 hexanes:ethyl acetate) to provide the title compound as a yellow oil (0.46 g, 91%).
Reaction SMILES: [C:1]([NH:4][CH2:5]/[CH:6]=[C:7]1\[CH2:8][CH2:9][CH2:10][C:11]2[C:16]\1=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)/C(=C/CNC(C)=O)CCC2
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)C(CCNC(C)=O)CCC2
Yield: 88.9 %

Procedure:
To a solution of (E)-1-[2-(acetylamino)ethylidene]-7-methoxy-1,2,3,4tetrahydronaphthalene (2.55 g, 10 mmol) in ethanol (20 ml) was added 5% palladium/carbon (50% hydrous, 400 mg). The mixture was subjected to catalytic reduction at normal pressure under hydrogen atmosphere. After the completion of hydrogenation, the palladium/carbon was then filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (chloroform:methanol=98:2) to give the above-titled compound (2.2 g, yield 86%, oil).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1.C([O-])(O)=O.[Na+].[Br:16]Br>ClCCl>[Br:16][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: BrBr
Reactant: COc1cccnc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(Br)cnc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,3-dimethoxypyridine (4-1, 2.5 g, 18.0 mmol, 1.0 equiv) in dichloromethane:saturated NaHCO3 (80 mL: 40 mL) at 0° C. was added bromine (0.93 mL, 18.0 mmol, 1.0 equiv) and the reaction mixture was stirred for 2 h at 25° C. The reaction mixture was quenched with solid Na2SO3 (˜10 g) and the aqueous phase was extracted with dichloromethane (3×100 mL). The organic phase was dried over magnesium sulfate and concentrated. The residue was purified via normal phase chromatography (0 to 20% EtOAc in hexanes, silica) to afford the desired product (4-2) as an oil after concentration. ESI+MS[M+H]+C7H8NO2 calc'd 218.0. found 218.0.
Reaction SMILES: CO[C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O)=O>C[Cd]C>[CH3:6][C:6]([CH3:3])([C:5](=[O:11])[C:3]([CH3:5])([CH3:12])[C:9](=[O:10])[CH3:8])[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: C[Cd]C
Product: COC(=O)CC(C)(C)C(=O)C(C)(C)C(C)=O

Procedure:
Starting from dimethyl acetonedicarboxylate, dimethyl tetra-C-methylacetonedicarboxylate was obtained by methylation, and this was converted into the dicarboxylic acid methyl ester chloride and then methylated with dimethylcadmium. The methyl 2,2,4,4-tetramethyl-3,5-dioxohexanecarboxylate obtained was cyclized in the presence of sodium methanolate. The total yield (based on dimethyl acetonedicarboxylate) is 0.01% (Chem. Ber. 92, 2033 (1959)).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28]Cl.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C(F)=CC=CC=3F)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:28][C:27]3[C:26]([F:25])=[CH:33][CH:32]=[CH:31][C:30]=3[F:34])[N:13]=2)=[CH:23][CH:22]=1
Reactant: Fc1cccc(F)c1CCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3c(F)cccc3F)c(-c3ccc(Cl)cc3)c2CC1
Product: Fc1cccc(F)c1Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 18.7 %

Procedure:
The title compound (0.07 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 1 mmol) using 2,6-difluorobenzyl chloride (1.5 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2,6-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H18ClF2N3, 373.12. found, m/z 374.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.34-7.30 (m, 5H), 6.93-6.90 (m, 2H), 5.34 (s, 2H), 3.59-3.57 (m, 2H), 3.39-3.37 (m, 4H), 2.94-2.92 (m, 2H).
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]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([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]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(OC)c(OC)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3,4-dimethoxy-phenylboronic acid to give [1-(3,4-dimethoxy-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 391(MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][C:22]4[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1>C(Cl)Cl>[CH3:30][S:31]([NH:29][C:27]1[CH:26]=[CH:25][C:23]2[N:24]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]4)=[N:15][CH:16]=3)[S:21][C:22]=2[CH:28]=1)(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4ccc(N)cc4s3)cn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4ccc(NS(C)(=O)=O)cc4s3)cn2)CC1
Yield: 48.8 %

Procedure:
To 4-[5-(6-amino-benzothiazol-2-yl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (12.7 mg, 0.031 mmol) in DCM (1 mL) was added methanesulfonyl chloride (3 μL, 0.034 mmol) followed by pyridine (3 μL, 0.034 mmol). The r.m. was stirred o.n. at r.t. The crude mixture was purified by flash column chromatography (heptane:ethyl acetate; 50:50 to 40:60), to give intermediate tert-butyl 4-(5-{6-[(methylsulfonyl)amino]-1,3-benzothiazol-2-yl}pyridin-2-yl)piperazine-1-carboxylate (7.4 mg) as a solid. MS m/z (M+H) 490, (M−H) 488. This intermediate was dissolved in DCM (1 mL) and TFA (300 μL) was added. The reaction mixture was thereafter stirred for three hours at r.t. The solvent was removed in a stream of nitrogen and the residue was dissolved in DMF (400 μL) and purified by prep. HPLC, to give the title compound (3 mg) as a white solid. 1H NMR δ 8.71 (d, 1 H) 8.09 (dd, 1 H) 7.72-7.86 (m, 2 H) 7.27 (dd, 1 H) 6.88 (d, 1 H) 3.63-3.77 (m, 4 H) 2.95-3.08 (m, 4 H) 2.90 (s, 3 H); MS m/z M+H 390, M−H 388.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][C:23](=[O:47])[CH:24]2[CH2:29][CH2:30][O:31][C:32](=[O:46])[N:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH3:48][Mg]Br.C(OCC)(=O)C.O>O1CCCC1>[Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][C:23]([OH:47])([CH3:48])[CH:24]2[CH2:29][CH2:30][O:31][C:32](=[O:46])[N:33]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([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
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC(=O)C2CCOC(=O)N(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(O)CCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc2C1CCOC(=O)N(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-t-butyldiphenylsilyloxy-1-[2-(N,N-diphenylcarbamoyloxy)ethyl]-2-oxo-1,2,3,4-tetrahydronaphthalene (0.9 g) in THF (tetrahydrofuran) (20 ml) was added methylmagnesium bromide (2.0 ml, 1M solution in THF) at 0° C. under N2. After being stirred for 1 hour at the room temperature, the solution was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 5-t-butyldiphenylsilyloxy-1-[2-(N,N-diphenylcarbamoyloxy)ethyl]-2-hydroxy-2-methyl-1,2,3,4-tetrahydronaphthalene (0.6 g).
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]([C:5]([OH:7])=O)([CH3:4])[CH3:3].Cl.C(N=C=NCCCN(C)C)C.[NH2:27][C@@H:28]([C:39]([N:41]1[CH2:48][CH2:47][CH2:46][C@@H:42]1[C:43]([OH:45])=[O:44])=[O:40])[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1.[CH2:49]([N-:53][CH2:54][CH:55]([CH3:57])[CH3:56])[CH:50]([CH3:52])[CH3:51]>C(Cl)Cl>[NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]([C:5]([NH:27][C@@H:28]([C:39]([N:41]1[CH2:48][CH2:47][CH2:46][C@@H:42]1[C:43]([OH:45])=[O:44])=[O:40])[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:7])([CH3:3])[CH3:4].[CH2:49]([N-:53][CH2:54][CH:55]([CH3:57])[CH3:56])[CH:50]([CH3:52])[CH3:51]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CC(C)C[N-]CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 18 h

Procedure:
In a 100 ml round bottom flask, 0.50 mmol of Boc-Aib (Aib=α-aminoisobutyric acid) was dissolved in 30 ml dry CH2Cl2 and then 0.51 mmol of 1-hydroxybenzotrizole was added while stirring under N2 atmosphere in an ice-bath, 0.55 mmol of 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide HCl was added in 20 ml dry CH2Cl2 at a fast drop rate and the reaction was stirred for 1 hour at 0° C. 0.51 mmol of (2) in 15 ml of CH2Cl2 was added dropwise and stirring was continued for a further 18 h at ambient temperature. The reaction mixture was washed with 20 ml of 20% citric acid aqueous solution, 20 ml of saturated NaCHO3 aqueous solution, and 20 ml of saturated sodium chloride aqueous solution. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Further purification was done by flash column chromatography (CHCl3/MeOH, 95:5) to afford white solid of Boc-Aib-DTrp-DPro-diisobutylamide.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([N:17]([CH3:19])[CH3:18])[N:10]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:25]([CH:29]=1)[C:26](O)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:25]([C:26]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([N:17]([CH3:18])[CH3:19])[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:27])[CH:29]=1
Reactant: COc1cc(N2CC3CNCC3C2)nc(N(C)C)n1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)nc(N(C)C)n1
Yield: 153.7 %

Procedure:
A mixture of [4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimethyl-amine (60.0 mg, 0.23 mmol), 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (52.0 mg, 0.25 mmol), HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68 mmol) was stirred into DMF (4.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (160.0 mg, 54%). MS (ESI) mass calcd. for C22H25FN8O2, 452.49; m/z found 453.3 [M+H]+. 1H NMR (CDCl3): 7.95 (dd, J=9.0, 4.8, 1H), 7.73 (s, 2H), 7.25-7.17 (m, 1H), 7.16-7.10 (m, 1H), 5.00-4.90 (m, 1H), 3.92-3.78 (m, 4H), 3.76-3.25 (m, 6H), 3.18-3.07 (m, 6H), 3.05-2.86 (m, 3H).