Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[NH:29][CH:28]=1.Cl>O1CCOCC1>[N:27]1([C:2]2[N:3]=[C:4]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[CH:28]1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: c1ccc2[nH]cnc2c1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C1CCN(Cc2cc3nc(-n4cnc5ccccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
A mixture of [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]dimethylamine (50 mg, 0.13 mmol), benzimidazole (32 mg, 0.27 mmol) and concentrated HCl (53 μL, 0.64 mmol) in 1,4-dioxane (1 mL) was subjected to microwave irradiation at 150° C. for 40 min. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (2 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: 2 M NH3 in MeOH 100:0 to 98:2 to 95:5 to 90:10) to afford 110 as a white solid (38 mg, 63%). LCMS (Method F): RT=5.12 min, [M+H]+ 478.2. 1H NMR (CDCl3, 400 MHz): δ 9.04 (s, 1 H); 8.61-8.57 (m, 1 H); 7.86-7.82 (m, 1 H); 7.43-7.31 (m, 2 H); 7.27 (s, 1 H); 4.07 (t, J=4.8 Hz, 4 H); 3.92 (t, J=4.8 Hz, 4 H); 3.82 (s, 2 H); 3.08-2.99 (m, 2 H); 2.30 (s, 6 H); 2.20-2.10 (m, 3 H); 1.88-1.78 (m, 2 H); 1.66-1.54 (m, 2 H)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]1([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)n1ccnc1
Temperature: 25 °C
Yield: 10.9 %

Procedure:
A solution of imidazole (5.0 g, 0.074 mol), ethyl 2-bromopropanoate (7.6 ml, 0.06 mol) and K2CO3 (11.2 g, 0.08 mol) in DMF (120 ml) was heated at 90° C. for 2 h. After this time the solution was cooled to room temperature, filtered and the filtrate diluted with EtOAc (200 ml). The mixture was washed with water (2×20 ml) and the organic phase separated. The combined aqueous layers were washed with EtOAc (200 ml) and the combined organic layers washed with brine (200 ml). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica, eluting with CH2Cl2 :MeOH (95:5), to afford the ester (1.1 g, 9%) as a pale yellow oil. 1H NMR (250 MHz, CDCl3) δ 1.26 (3H, t, J=7.1 Hz), 1.75 (3H, d, J=7.3 Hz), 4.20 (2H, q, J=7.1 Hz), 4.85 (1H, q, J=7.3 Hz), 7.02-7.04 (1H, m), 7.08-7.10 (1H, m), 7.58 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]Cl)=[N:6][CH:7]=1.Cl.[CH3:11][O:12][NH2:13].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:13][O:12][CH3:11])=[N:6][CH:7]=1
Reactant: CON
Reactant: ClCc1ccc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CONCc1ccc(Br)cn1
Temperature: 60 °C
Yield: 28.5 %

Procedure:
To a stirred solution of 5-Bromo-2-chloromethyl-pyridine (2 g, 9.709 mmol) in dimethylformamide (30 mL) is added methoxy amine hydrochloride salt (0.973 g, 11.65 mmol) and K2CO3 (3.35 g, 24.27 mmol) at room temperature then heated to 60° C. for 16 hours. Reaction mixture diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combiflash using 30% ethyl acetate in hexane as an eluent to afford the title compound (0.6 g). 1HNMR (400 MHz, DMSO-d6) δ: 3.36 (s, 3H), 3.99 (d, J=5.88 HZ, 2H), 7.10 (t, 1H), 7.44-7.46 (dd, J1=8.32 Hz, J2=0.32 Hz, 1H), 7.99-8.02 (dd, J1=2.44 Hz, J2=8.4 Hz, 1H), 8.60-8.61 (dd, J1=2.4 Hz, J2=0.4 Hz, 1H). LC-MS (m/z): [M+H]=217.1.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.Br[CH2:30][CH:31]=[CH2:32]>>[CH2:32]([O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: C=CCOCCCc1c[nH]cn1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 5 mmol of 3-bromo-1-propene are treated as described in Example 5. The title compound is crystallized in the form of the hydrogen oxalate from ethanol and diethyl ether.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH:10]=[C:11]([S:13][CH2:14][CH3:15])[N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:14]([S:13][C:11]1[N:12]=[C:8]([NH2:7])[S:9][CH:10]=1)[CH3:15]
Reactant: CCSc1csc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCSc1csc(N)n1
Reaction time: 3 h
Yield: 71.3 %

Procedure:
(4-Ethylsulfanyl-thiazol-2yl)-carbamic acid tert-butyl ester (0.583 g, 2.24 mmole) was dissolved in methylene chloride (9 mL) and the resulting solution was cooled in an ice-water bath. Trifluoroacetic acid (5 mL) was added dropwise to this solution. The solution was stirred under an argon atmosphere for 3 hours, allowing the cooling bath to slowly warm up. At the conclusion of the reaction, the bath temperature was 12° C. The reaction was concentrated. The residue was redissolved in methylene chloride and concentrated. This was repeated two additional times to remove most of the trifluoroacetic acid. Following the final concentration, the residue was dissolved again in methylene chloride and washed with saturated sodium bicarbonate, water and brine. The organic phase was dried over sodium sulfate and concentrated to yield 4-ethylsulfanyl-thiazol-2-ylamine (0.256 g, 65%).
Reaction SMILES: C(O[CH2:9][C@@H:10]1[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C:11]1=O)C1C=CC=CC=1.[CH2:24]([Al](CC(C)C)CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:16]([O:15][CH2:14][C:13]1[CH:10]=[CH:9][CH:24]=[CH:11][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Reactant: O=C1C[C@H](COCc2ccccc2)[C@H]1COCc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(COCc2ccccc2)cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A solution of (2S-trans)-2,3-bis[(benzyloxy)methyl]cyclobutanone (0.2 g., 0.645 mmole) in toluene (4 ml.) was added dropwise over 10 minutes to a solution of triisobutylaluminum (0.91 M in hexane, 0.9 ml., 0.816 mmole) in toluene (2 ml.) at -40° C. The mixture was stirred at -50° C. for 4 hours and at -40° C. for one hour. A solution of triisobutylaluminum (1 ml., 0.91 mmole) was added to the reaction mixture. After stirring for 30 minutes the reaction was quenched by adding 10% hydrochloric acid (2 ml.) at -40° C. The organic phase was washed with brine, dried (magnesium sulfate), and the solvent was evaporated to give [1S-(1α,2β,3β)]-3-hydroxy-1,2-cyclobutanedimethanol, dibenzyl ether; TLC (30% ethyl acetate/hexane) Rf =0.3. The product contained about 5% of the isomeric compound; TLC (30% ethyl acetate/hexane) Rf =0.2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:8][C:7]2=[O:18])(=[O:3])[CH3:2].[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.[Cl-].[NH4+]>[CH2:14]([C:9]1[NH:10][C:11]2[C:6]([C:7](=[O:18])[N:8]=1)=[CH:5][C:4]([C:1]([OH:3])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:2])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH3:17]
Reactant: Br[Mg]c1ccccc1
Reactant: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(C)(O)c3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.08 g of 6-acetyl-2-butyl-4(1H)-quinazolinone in 80 ml of tetrahydrofuran is added dropwise at room temperature 14.2 ml of 3.0M phenylmagnesium bromide. The reaction mixture is stirred at room temperature overnight then diluted with aqueous ammonium chloride and extracted with chloroform. The organic layer is dried and evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 1:1 ethyl acetate-hexanes to give 0.535 g of the desired product as a solid. Cl MASS SPEC 323 (MH+).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1COCC1.[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30](=[O:33])[CH2:31][CH3:32])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.[C:36]([Si:40]([CH3:43])([CH3:42])Cl)([CH3:39])([CH3:38])[CH3:37]>O>[C:36]([Si:40]([O:33]/[C:30](/[C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:21]2[CH:34]=[CH:35][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[CH:25][CH:26]=1)=[CH:31]\[CH3:32])([CH3:43])[CH3:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC(=O)c1ccc(OCc2ccc(OC)cc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C/C=C(\O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
With cooling with ice, potassium hexamethyldisilazide (0.5 M toluene solution, 89 mL) was dropwise added to a stirring THF (100 mL) solution of the compound (10.0 g, 37.0 mmol) synthesized in the above (1) and t-butyldimethylchlorosilane (6.13 g, 40.7 mmol), and then the reaction solution was stirred at room temperature for 12 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated saline, and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane) to obtain the entitled compound (13.5 g, 95%) as a white solid.
Reaction SMILES: CC(CC)C(O)=[O:4].[CH3:8][CH:9]([CH2:24][CH3:25])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11].O.C(=O)([O-])O.[Na+]>CO>[OH:4][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH:9]([CH3:8])[CH2:24][CH3:25])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1
Reactant: CCC(C)C(=O)O
Reactant: CCC(C)C(=O)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(C)C(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 87.9 %

Procedure:
0.67 g of the above 2-methylbutanoic acid-4-(2-methylbutanoyl) biphenyl was mixed with 95 ml of methyl alcohol and 5 ml of water and added with 1.14 g (13.6 mmol) of sodium hydrogen carbonate with stirring, which was subjected to hydrolysis reaction at room temperature for 40 hours. After the completion of the reaction, methanol was distilled off and 1 normal hydrochloric acid was added to adjust pH to not more than 1, and the extraction with dichloromethane was performed. The extracted liquid was washed with water, dried on anhydrous sodium sulfate and purified by a column chromatography of silica gel after the removal of the solvent to obtain 0.44 g (yield 88%) of (+)-4-hydroxy-4'-(2-methylbutanoyl) biphenyl at a light yellow crystal having the aforementioned properties.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([OH:17])[N:11]=[CH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([O:17][CH3:20])[N:11]=[CH:10]2)=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1c(O)ncn1Cc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ncn(Cc2ccc([N+](=O)[O-])cc2)c1C(N)=O
Temperature: 50 °C

Procedure:
3.93 g (15 mmol) of the derivative 3-(4-nitrobenzyl)-5-hydroxy-3H-imidazole-4-carboxamide are added to 80 ml of DMF in a three-necked flask under argon, followed by addition of 8.29 g (60 mmol; 4 eq.) of potassium carbonate. The stirred medium is maintained at 50° C. for 30 minutes and then cooled to room temperature. Methyl iodide (5.75 g; 40.5 mmol; 2.7 eq.) is then added.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[Br:16][C:17]1[C:22]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:21][CH:20]=[C:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:18]=1.CN1C(=O)CCC1>C1COCC1>[Br:16][C:17]1[C:22]([CH:23]=[CH:24][C:25]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:26])=[CH:21][CH:20]=[C:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:18]=1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)c(Br)n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C=CC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)c(Br)n1
Yield: 32.7 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (116 mg, 0.454 mmol) was reacted with 3-(2-bromo-6-tert-butyl-pyridin-3-yl)-acrylic acid (1.0 eq, 129 mg) DMTMM (1.0 eq, 126 mg) and NMP (1.2 eq, 60 μl) in THF to give the title compound (72 mg, 32.8%) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[Br:18][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[O:9][C:8]([CH3:13])([CH3:12])[CH2:7][CH:6]2[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C1CC(C)(C)Oc2cc(F)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1CC(C)(C)Oc2cc(F)c(Br)cc21
Temperature: 50 °C
Yield: 93.2 %

Procedure:
Methyl 7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromene-4-carboxylate (187 mg, 0.785 mmol) was diluted with DMF (5 mL) followed by the addition of N-bromosuccinimide (154 mg, 0.863 mmol). The reaction was heated at 50° C. for 2.5 hours. The reaction was cooled, diluted with ethyl acetate and washed with water, saturated sodium bicarbonate, water, and brine. The organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a Biotage 40M cartridge, gradient 5% ethyl acetate/hexane to 50% to yield the title compound (232 mg, 93.2% yield).
Reaction SMILES: [Li+].[BH4-].CON(C)[C:6](=[O:41])[CH:7]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:19]=2)=[CH:13][C:12]=1[Cl:32].O.[CH2:44]1COCC1>C(O)C>[CH2:25]([O:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][CH:7]([NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH:6]([OH:41])[CH3:44])=[C:12]([Cl:32])[CH:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)C(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Product: CC(O)C(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiBH4 (50 mg) was added to the compound of Example 130 in a mixture of THF (15 mL) and ethanol (3 mL). The mixture was stirred at room temperature for 1 hour. Following addition of water, the mixture was extracted with ethyl acetate and the extract was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. The solvent was concentrated and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product as a colorless oil (320 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].Cl.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>CO>[NH:14]1[CH2:15][CH:16]=[C:17]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:18][CH2:19]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C1=C(c2c[nH]c3ccccc23)CCNC1
Temperature: 25 °C

Procedure:
30 g (0.26 mol) of indole were dissolved in a solution of potassium hydroxide (77.6 g, 1.38 mol) in methanol (692 ml). 4-piperidone monohydrate hydrochloride (102.3 g, 0.66 mol) was added in one portion and the mixture was heated to reflux for 5 h. Potassium chloride precipitated upon cooling at room temperature and it was filtered off. The liquid phase was concentrated until only one third of the liquid remained in the round-bottom flask. The solid formed during the concentration of the liquid phase was filtered and washed thoroughly with ethanol and, finally, with ethyl ether. 31.9 g (63% of yield) of the final product were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-])=O)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[H][H]>[Ni].CO>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][CH2:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][CH:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:9])[CH2:15][CH2:14]1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCNc2ccccc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1ccccc1NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 100 %

Procedure:
A mixture of 27 parts of (4-fluorophenyl) [1-{3-[(2-nitrophenyl)amino]propyl}-4-piperidinyl]methanone in 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over hyflo and the filtrate is evaporated, yielding 25 parts (100%) of [1-{3-[(2-aminophenyl)amino]-propyl}-4-piperidinyl] (4-fluorophenyl)methanone as a residue.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][C:11]#[N:12].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:14]1([CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][C:11]#[N:12]
Reactant: Cc1ccccc1B(O)O
Reactant: N#CCCNc1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1NCCC#N

Procedure:
The title compound was prepared in analogy to example 72, from 3-(4-iodo-pyridin-3-ylamino)-propionitrile and 2-methylphenylboronic acid (CAS RN 16419-60-6) and using a gradient of heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown solid (81%). MS (ESI): m/z=238.13 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.[NH2:25][N:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](/[C:22](=[N:25]/[N:26]3[CH2:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])/[CH3:23])[N:20]=2)[N:15]=[N:14]1
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Reactant: NN1CC(=O)NC1=O
Product: C/C(=N\N1CC(=O)NC1=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 71.5 %

Procedure:
The title compound (18.0 mg, 66%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (20.0 mg, 0.06 mmol) and 1-amino-imidazolidine-2,4-dione (28.2 mg, 0.19 mmol) using the same procedure as described in the synthesis of example 72. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.45 (bs, 1H), 9.41 (s, 1H), 8.93 (dd, 1H), 8.42 (d, 1H), 8.21 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 6.26 (s, 2H), 4.56 (s, 2H), 2.45 (s, 3H). LCMS (method B): [MH]+=420, tR=1.95 min.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.[NH:22]([CH3:47])[C@H:23]([C:27]([N:29]([CH3:46])[C@H:30]([C:43]([NH2:45])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:33]=1)=[O:28])[CH:24]([CH3:26])[CH3:25].O>C1COCC1>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([N:22]([CH3:47])[C@H:23]([C:27]([N:29]([CH3:46])[C@H:30]([C:43]([NH2:45])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:40])[CH3:41])[CH:33]=1)=[O:28])[CH:24]([CH3:26])[CH3:25])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(F)c1)C(=O)O
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(O)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 27 h
Yield: 9.7 %

Procedure:
To a solution of the above crude Boc-Tyr(3-F)-OH (1.18 g), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (1.10 g, 3.03 mmol) and CMPI (1.16 g, 4.55 mmol) in THF (6 ml), TEA (1.27 ml, 12.1 mmol) was added under cooling with ice and stirred at room temperature for 27 hours. The reaction mixture was mixed with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:concentrated aqueous ammonia=30:1:0.05), giving the titled compound (0.19 g, 10%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:11][O:10][CH2:9]2)[C:4](=[O:12])[CH:3]=1.[OH:13][C:14]([CH3:47])([CH3:46])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH3:24])[CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>COCCOC.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>[OH:13][C:14]([CH3:46])([CH3:47])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:26]=[CH:27][C:28]([C:2]3[CH:7]=[CH:6][N:5]([CH:8]4[CH2:11][O:10][CH2:9]4)[C:4](=[O:12])[CH:3]=3)=[CH:29][CH:30]=2)[CH3:24])[CH2:18][CH2:17]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1cc(Br)ccn1C1COC1
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: C[C@@H](c1ccc(-c2ccn(C3COC3)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pd(PPh3)4 (10 mg) was added to a solution of 4-bromo-1-(oxetan-3-yl)pyridin-2(1H)-one (14 mg) in 1,2-dimethoxyethane (6 mL) under nitrogen. The formed mixture was stirred at room temperature for 1 h prior to the addition of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one (24 mg) in ethanol (2 mL) followed by saturated aqueous NaHCO3 solution (2 mL). The mixture was stirred at 100° C. for 2 h. After cooling to room temperature, the reaction was quenched with water and the resulting mixture was extracted with ethyl acetate (3×). The combined organic phase was concentrated and the residue was purified by preparative HPLC to give the title compound. Yield: 14 mg (55% of theory); LC (method 4): tR=0.97 min; Mass spectrum (ESI+): m/z=445 [M-Me2CO+H]+; 1H NMR (CDCl3) δ 1.09 (s, 3H), 1.12 (s, 3H), 1.45 (d, 3H), 2.10-2.30 (m, 4H), 2.35 (m, 1H), 2.72 (m, 1H), 4.70 (m, 2H), 5.09 (m, 2H), 5.63 (m, 1H), 5.71 (m, 1H), 6.43 (m, 1H), 6.61 (m, 1H), 6.98 (d, 2H), 7.28 (m, 7H), 7.61 (d, 1H).