Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([N:14]=[C:15]=[S:16])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl.[C:31]([NH2:39])(=[NH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCOC(/N=N/C(OCC)=O)=O>CN(C=O)C>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:16][N:39]=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:38]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N=C(N)c1ccccc1
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=S
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(-c2ccccc2)ns1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.1 %

Procedure:
A mixture of 2-(2-tert-butylphenoxy)-3-isothiocyanatopyridine (Example 1a) (100 mg, 0.35 mmol), diisopropylethylamine (186 μL, 1.05 mmol) and benzamidine hydrochloride (55 mg, 0.35 mmol) in DMF (2 mL) was stirred at rt for 18 h. Diethylazodicarboxylate (110 μL, 0.7 mmol) was added and mixture was stirred for 4 h. The reaction mixture was purified by preparative HPLC to give the title compound (110 mg, TFA salt) as a white solid. (M+H)+=403. 1H NMR (400 MHz, DMSO d6) δ ppm 1.31 (s, 9H), 6.94 (dd, J=7.83, 1.26 Hz, 1H), 7.16 (dd, J=7.58, 1.26 Hz, 1H), 7.20-7.27 (m, 2H), 7.44 (dd, J=8.09, 1.77, 1H), 7.48-7.56 (m, 3H), 7.79 (dd, J=4.80, 1.51 Hz, 1H), 8.20 (dd, J=7.83, 1.52 Hz, 2H), 9.04 (dd, J=7.83, 1.52 Hz, 1H), 10.93 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.C[O:23][C:24](=O)[C:25]([CH3:28])([CH3:27])[NH2:26]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:24](=[O:23])[C:25]([CH3:28])([CH3:27])[NH:26][C:12]2=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)(C)N
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)NC(=O)N(c2ccc(C(C)(C)C)cc2)C1=O
Temperature: 25 °C
Yield: 79.6 %

Procedure:
To a suspension of 15 g of 4-tert-butylphenyl-isocyanate in 200 mL of toluene are successively added 31.52 mL of triethylamine and 13.15 g of 2,2-dimethylglycine methyl ester hydrochloride. The reaction mixture is refluxed for 24 h, cooled to room temperature, poured into distilled water and extracted with ethyl acetate. The organic phase is washed successively with water and with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is taken up in diethyl ether and the solid formed is filtered off and dried to give 17.75 g of 3-(4-tert-butylphenyl)-5,5-dimethyl-imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][CH:2]([Cl:26])[C:3]([NH:5][C@H:6]([CH2:24][F:25])[C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]([CH2:21][C:22]#[N:23])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)[OH:8])=[O:4].S(=O)(=O)(O)[OH:28].C(=O)(O)[O-].[Na+]>>[NH2:23][C:22](=[O:28])[CH2:21][C:18]1[N:17]=[CH:16][C:15]([C:12]2[CH:11]=[CH:10][C:9]([C@@H:7]([OH:8])[C@H:6]([NH:5][C:3](=[O:4])[CH:2]([Cl:1])[Cl:26])[CH2:24][F:25])=[CH:14][CH:13]=2)=[CH:20][CH:19]=1
Reactant: N#CCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: NC(=O)Cc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1

Procedure:
The product of step 3 of Example 4 (10 mg, 0.025 mmol) is stirred with concentrated sulfuric acid (0.5 mL) at room temperature for 30 minutes. The solution is basified with saturated aqueous sodium bicarbonate (5 mL) and extracted with 10% methanol in CH2Cl2 (10 mL). The organics are concentrated and the residue purified by chromatography on a reverse phase C-18 column eluting with a gradient of neat water with 0.1% trifluoroacetic acid to neat acetonitrile with 0.1% trifluoroacetic acid to give the title compound (2 mg): m/z (Cl) 415 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[NH2:24])[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.O.[Br].[N:27]#[C:28]C#N>C(O)(=O)C>[NH2:27][C:28]1[NH:24][C:23]2[CH:22]=[CH:21][C:4]([O:5][CH2:6][CH2:7][N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(N)c(N)c2)CC1
Reactant: N#CC#N
Agent: [Br]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc3[nH]c(N)nc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
A 100 mL flasked was charged of tert-butyl 4-(2-(3,4-diaminophenoxy)ethyl)piperazine-1-carboxylate (1.53 g, 4.54 mmol), water (50 mL) and acetic acid (2 mL) and stirred at room temperature for 15 minutes. The reaction mixture was placed in an ice bath and then charged with cyanogen bromine (0.526 g, 5 mmol) and continued to stir at 0° C. The reaction temperature was allowed to warm to room temperature and it was stirred over night. The reaction was completed as determined by LCMS. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in acetone, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.7 g of tert-butyl 4-(2-(2-amino-1H-benzo[d]imidazol-5-yloxy)ethyl)piperazine-1-carboxylate as a di-acetate salt as black foam. MS (EI): 362 (MH+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].CS(O[CH:18]1[CH2:21][N:20]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19]1)(=O)=O.CCN(C(C)C)C(C)C>CC#N>[CH:22]([N:20]1[CH2:21][CH:18]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:1])([F:11])[F:12])[CH2:6][CH2:7]2)[CH2:19]1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(N1CCNCC1)C(F)(F)F
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1)C(F)(F)F

Procedure:
To a solution of 2,2,2-trifluoro-1-piperazin-1-yl-ethanone (6 g, 32.94 mmol) and 1-benzhydrylazetidin-3-yl methanesulfonate (12.5 g, 39.38 mmol) in CH3CN (60 mL) was added DIPEA (12 mL, 68.89 mmol) at room temperature. The resulting mixture was refluxed for 2 h. The solvent was removed by evaporation and the residue was partitioned between CH2Cl2 and aq NaHCO3. The organic layer was washed with aq NaHCO3 (2×) and then extracted with 1N HCl (2×). The aqueous layer was cooled and then the pH adjusted with 1N NaOH until basic (pH=10). The resulting mixture was extracted with CH2Cl2 (2×). The organic layer was dried over MgSO4 and concentrated. The title compound was purified by reverse phase chromatography. MS m/z (M+H+) 404.2.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN1CCOCC1>C(Cl)Cl>[CH2:28]([NH:35][C:36]([N:7]1[CH2:6][CH2:5][C:4]([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])([C:2]#[N:3])[CH2:9][CH2:8]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(C(=O)NCc2ccccc2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and benzyl isocyanate in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [O:1]([CH:8]=[CH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(C(OO)=[O:24])=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[O:1]([CH:8]=[CH:9][CH2:10][C:11]12[O:24][CH:16]1[CH:15]=[CH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1ccccc1
Reactant: C(=COc1ccccc1)Cc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C1=CC2OC2(CC=COc2ccccc2)C=C1
Reaction time: 96 h
Yield: 58 %

Procedure:
5.8 g of o-phenoxyallylbenzene was added to 70 ml of chloroform solution containing perbenzoic acid prepared from 17 g of benzoyl peroxide and the mixture was allowed to stand at about 5° C for 4 days. The resulting mixture was washed with sodium hydroxide solution, Mohr's salt solution, then water and dried on anhydrous sodium sulfate. The solvent was evaporated and the concentrated was chromatographed over a silica gel, eluted with benzene, there was obtained 3.6 g (yield 58%) of o-phenoxyallylbenzene oxide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([CH3:15])([OH:14])[CH3:13].[H-].[Na+].[NH2:18]OS(O)(=O)=O>CN(C=O)C.CCOC(C)=O>[NH2:18][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])=[CH:6]1
Reactant: NOS(=O)(=O)O
Reactant: CC(C)(O)Cc1c[nH]c2ccc(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(O)Cc1cn(N)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(5-fluoro-1H-indol-3-yl)-2-methyl-propan-2-ol (207 mg, 1 mmol) in DMF (10 mL) is cooled to 0° C., treated with NaH (600 mg, 15 mmol, 60% in mineral oil) and stirred for 30 min. H2NOSO3H (565 mg, 5 mmol) is added portion wise, and the mixture is warmed to rt over 2 h. The mixture is diluted with EtOAc (100 mL), quenched with water, extracted with EtOAc, dried (Na2SO4), filtered and concentrated in vacuo to afford 1-(1-amino-5-fluoroindol-3-yl)-2-methyl-propan-2-ol, which is used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][C@@H:11]3[CH2:14][CH2:15][CH2:16][N:10]3[C:9](=[O:17])[C:8]=2[CH:18]=1)([O-])=O.CO.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][C@@H:11]3[CH2:14][CH2:15][CH2:16][N:10]3[C:9](=[O:17])[C:8]=2[CH:18]=1
Reactant: [H][H]
Reactant: O=C1c2cc([N+](=O)[O-])ccc2OC[C@@H]2CCCN12
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)N1CCC[C@H]1CO2
Yield: 93.8 %

Procedure:
A solution of (S)-7-nitro-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzoxazepine-5-one (7.4 g), prepared as described in Example 3L, in ethanol (100 ml) and methanol (50 ml) was hydrogenated over 10% palladium on activated carbon under 2 bar hydrogen, until the uptake of hydrogen ceased. The mixture was filtered to remove the catalyst and evaporated to dryness in vacuo. The crude product was passed through a short silica column (eluting with 10% methanol in dichloromethane) to give the title product (6.1 g). EIMS: m/z=219 [M+H]+
Reaction SMILES: CCOCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=1.[F:15][C:16]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:17]=1[C:18](N(OC)C)=[O:19]>C1COCC1>[F:15][C:16]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:17]=1[C:18]([C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1)=[O:19]
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccc(F)cc1)c1cccc(C(F)(F)F)c1F
Temperature: 50 °C
Yield: 0.7 %

Procedure:
2M Et2O solution of 4-fluorophenylmagnesium bromide (32.5 ml; 65 mmol) was added to a solution of 12.8 g (65 mmol) of 2-fluoro-N-methoxy-N-methyl-3-trifluoromethyl-benzamide in 150 ml of THF at 0° C. The reaction mixture was heated overnight at 50° C. The reaction mixture was partitioned with EtOAc and H2O. The organic phases were washed with brine and dried over Na2SO4. The resulting ketone (135 mg) was obtained after flash chromatographic purification using hexane/CH2Cl2 (3:1, v/v) as an eluent.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[CH2:23]Br>>[CH3:29][O:28][C:26]1[CH:25]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:27]=1)[CH2:23][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: COc1cc(CBr)cc(OC)c1
Product: COc1cc(CN2N(C3C4CC5CC(C4)CC3C5)C(=O)C2(C)C)cc(OC)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3,5-dimethoxybenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [O:1]1[CH2:5][C@@H:4]([OH:6])[C@H:3]2[O:7][CH2:8][C@@H:9]([OH:10])[C@@H:2]12.N12CCCN=C1CCCCC2.[Cl:22][C:23]1[CH:24]=[C:25]2[N:32]=[C:31](S(C)(=O)=O)[N:30]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:26]2=[N:27][C:28]=1[I:29]>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]2[N:32]=[C:31]([O:6][C@H:4]3[C@H:3]4[O:7][CH2:8][C@@H:9]([OH:10])[C@H:2]4[O:1][CH2:5]3)[N:30]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:26]2=[N:27][C:28]=1[I:29]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(Cl)c(I)nc21
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(I)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3R,3aR,6R,6aR)-Hexahydrofuro[3,2-b]furan-3,6-diol (1.84 g) is dissolved in N,N-dimethylformamide (10 mL) and treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 1.9 mL). A solution of 6-chloro-5-iodo-2-(methylsulfonyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridine (2.05 g) in N,N-dimethylformamide (20 mL) is added dropwise and the mixture is stirred for 2 hours at room temperature. The mixture is partitioned between water and ethylacetate and the organic phase is washed with brine and dried (MgSO4). The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→0:100) to give the title compound. LC (method 1): tR=1.17 min; Mass spectrum (ESI+): m/z=554 [M+H]+.
Reaction SMILES: [CH:1]1([C@H:4]2[CH2:9][N:8]([C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]4[CH2:19][CH2:20][CH2:21][C:11]=34)[CH2:7][C@@H:6]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C@@H:5]2[OH:30])[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl.O>[CH:1]1([C@H:4]2[CH2:9][N:8]([C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N+:13]([O-:39])=[C:12]4[CH2:19][CH2:20][CH2:21][C:11]=34)[CH2:7][C@@H:6]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C@@H:5]2[OH:30])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@H](C2CC2)[C@H]1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C[C@H](C2CC2)[C@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
A solution of tert-butyl [(3R,4R,5S)-5-cyclopropyl-4-hydroxy-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (0.113 g, 0.270 mmol) in anhydrous DCM (2.5 mL) was cooled to 0° C. and mCPBA (0.080 g, 0.33 mmol, 4×0.020 g) was added portion-wise. After 15 min., the reaction mixture was allowed to warm to ambient temperature and was stirred for 2 h. The reaction was quenched by the addition of a solution of Na2S2O3 (0.051 g, 0.32 mmol) in water (1 mL) followed by 4 M aq. NaOH (1 mL). The layers were separated and the organic fraction was concentrated and purified by flash column chromatography (20 g silica gel column, eluting with 0-30% MeOH/EtOAc) to afford the sub-title compound (0.050 g, 43%). LCMS (ESI) m/z calc. for C21H31N4O6 435.2 [M+H]+. found 435.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C([O-])([O-])=O.[Na+].[Na+].O.[C:15](Cl)([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16]>O1CCOCC1.[Na+].[Cl-]>[O:7]=[C:2]1[NH:1][CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][CH:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:16])[CH2:3]1
Reactant: O=C1CNCCN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
To a solution of piperazin-2-one (2 g, 20 mmol, 1 equiv), Na2CO3 (4.2 g, 40 mmol, 2 equiv) and water (20 mL) in 1,4-dioxane (60 mL) was added Fmoc-Cl (5.7 g, 22 mmol, 1.1 equiv) at 0° C. After the reaction mixture was stirred at room temperature for 4 h, it was diluted with saturated NaCl (200 mL). The solution was extracted with ethyl acetate (3×50 mL) and dried over Na2SO4. The combined organic layers were concentrated to give 6.7 g of the desired product, which was directly used for the next step without further purification. MS (ESI): 323 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29](B(O)O)[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:20]([O:19][C:17]([NH:16][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:27]2[CH:26]=[C:25]([F:24])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])=[CH:3][CH:4]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: COc1ccc(F)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of (R)-ethyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate, (3.12 g, 8.08 mmol), and 5-fluoro-2-methoxyphenylboronic acid (2.2 g, 12.93 mmol) in toluene (52 mL) and is added PdCl2(dppf)CH2Cl2 adduct (0.66 g, 0.81 mmol) and 2M aq. Na2CO3 (8.1 mL, 16.16 mmol). After stirring at 95° C. under nitrogen for 4 hours, the solution is cooled to ambient temperature and then quenched with ice water. The crude is diluted with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 50:50) to give (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(5′-fluoro-2′-methoxybiphenyl-4-yl)butanoate (2.86 g). HPLC retention time=1.80 minutes (condition A); MS (m+1)=432.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J=7.1 Hz, 3 H) 1.45 (s, 9 H) 2.45-2.65 (m, 2 H) 2.83-2.94 (m, 1 H) 2.94-3.09 (m, 1 H) 3.80 (s, 3 H) 4.20 (q, J=7.2 Hz, 2 H) 4.24-4.33 (m, 1 H) 5.11 (br. s., 1 H) 6.90-6.96 (m, 1 H) 7.00 (dd, J=7.8, 3.3 Hz, 1 H) 7.06 (dd, J=9.2, 3.2 Hz, 1 H) 7.27 (d, J=7.8 Hz, 2 H) 7.49 (d, J=7.8 Hz, 2 H)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:17]=[CH:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:31])=[CH:8][C:7]=2[O:32][CH3:33])[CH2:2]1.[C:34]1(=O)[CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH:34]1([N:1]2[CH2:4][CH:3]([O:5][C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]5[N:18]=[C:19]([C:21]6[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=6)[S:20][C:14]=5[C:13]4=[O:31])=[CH:8][C:7]=3[O:32][CH3:33])[CH2:2]2)[CH2:37][CH2:36][CH2:35]1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(C(F)(F)F)cc4)sc3c2=O)ccc1OC1CNC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(-n2ccc3nc(-c4ccc(C(F)(F)F)cc4)sc3c2=O)ccc1OC1CN(C2CCC2)C1
Reaction time: 8 h
Yield: 39.5 %

Procedure:
Dissolve 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-trifluoromethyl-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (0.909 g, 1.92 mmol) in dichloroethane (25 mL) and add cyclobutanone (0.502 mL, 6.72 mmol), sodium triacetoxyborohydride (0.814 g, 3.84 mmol), and acetic acid (0.22 mL, 3.84 mmol). Stir the mixture overnight, add saturated sodium bicarbonate, and extract with dichloromethane (3×). Dry the mixture using sodium sulfate, filter, and concentrate. Purify via silica gel chromatography using a 0-4.5% gradient of 2N ammonia in methanol/dichloromethane to give 0.400 g (39%) of the desired product. MS/ES m/z 528.0 [M+1]+.
Reaction SMILES: Cl.[N:2]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([C:24]([OH:26])=O)=[CH:18]3)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:49][C:50]1([F:56])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:49][C:50]1([F:56])[CH2:55][CH2:54][N:53]([C:24]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[CH2:7][N:2]2[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:14])=[CH:23][CH:22]=3)=[O:26])[CH2:52][CH2:51]1
Reactant: FC1(F)CCNCC1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4,4-difluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow solid (74%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24]>CN(C)C=O>[F:27][C:22]([F:28])([C:23]([F:26])([F:25])[F:24])[CH2:21][CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: FC(F)(F)C(F)(F)CCI
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)C(F)(F)F)Cc1ccc(C(F)(F)F)cc1
Yield: 60.6 %

Procedure:
Using 0.30 g of (4-(trifluoromethyl)benzyl)malononitrile, 6 ml of N,N-dimethylformamide, 0.60 g of sodium hydride (60% in oil), and 0.38 g of 4-iodo-1,1,1,2,2-pentafluorobutane, and according to the process described in the Production Example 1, there was obtained 0.30 g of 2-(3,3,4,4,4-pentafluorobutyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (8)).