Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH:24]([NH2:26])[CH3:25])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[CH:24]([NH:26][C:10](=[O:12])[C:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)([CH3:14])[CH3:13])[CH3:25])=[CH:19][CH:18]=1
Reactant: CC(N)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: Cc1ccc(OC(C)(C)C(=O)O)cn1
Agent: Cl
Product: Cc1ccc(OC(C)(C)C(=O)NC(C)C(Cc2ccc(Cl)cc2)c2ccc(Cl)cc2)cn1

Procedure:
The title compound was prepared by reacting 2-(6-methyl-3-pyridyloxy)-2-methylpropionic acid (Step B, 75 mg, 0.63 mmol) with 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt (Diastereomer α, Reference Example 1) (0.23 g, 0.63 mmol) following the procedure described in Example 62-63. LC-MS: m/e 471 (M+H)+ (3.1 min).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][C:4]=2[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c(s1)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
Into a 100-mL round-bottom flask charged with 5-tert-butyl 2-ethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (1 g, 3.21 mmol; prepared as described in J. Med. Chem. 2006, 49(15):4623-4637) and DCM (16 mL) was slowly added trifluoroacetic acid (1.48 mL, 19.3 mmol) at 0° C. The solution was then stirred at room temperature for 60 min. To the reaction mixture was then added saturated aqueous NaHCO3 solution (10 mL) and DCM (10 mL). Upon separation of the layers, the aqueous solution was further extracted with DCM (20 mL) twice. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated to give ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (0.547 g, 81%) as an oil. LCMS: (FA) ES+ 212.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[CH:16]=2)=[N:6]1.[Cl:18][C:19]1[CH:24]=[C:23](F)[CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:19]1[CH:24]=[C:23]([N:2]([CH3:1])[CH2:3][CH2:4][N:5]2[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]3[S:13][CH:14]=[C:15]([CH3:17])[CH:16]=3)=[N:6]2)[CH:22]=[CH:21][N:20]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: CNCCn1nc(-c2cc(C)cs2)ccc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(-c2ccc(=O)n(CCN(C)c3ccnc(Cl)c3)n2)c1
Temperature: 75 °C

Procedure:
A suspension of 2-(2-(methylamino)ethyl)-6-(4-methylthiophen-2-yl)pyridazin-3(2H)-one (200 mg, 802 μmol), 2-chloro-4-fluoropyridine (116 mg, 882 μmol), and potassium carbonate (222 mg, 1604 μmol) in DMF (1 mL) was heated to 75° C. for 90 min. The reaction mixture was partitioned between CH2Cl2 (50 mL) and 5% NaHCO3 (20 mL). The organic layer was dried over MgSO4 and concentrated to a solid from toluene under reduced pressure. The solid was triturated with toluene and dried under reduced pressure to give a white solid. MS (ESI pos. ion) m/z (MH+): 361. Calc'd exact mass for C17H17ClN4OS: 360. 1H NMR (400 MHz, Chloroform-d) δ ppm 2.28 (s, 3 H) 3.02 (s, 3 H) 3.83 (t, J=6.27 Hz, 2 H) 4.40 (t, J=6.27 Hz, 2 H) 6.40-6.52 (m, 2 H) 6.85 (d, J=9.54 Hz, 1 H) 6.96 (s, 1 H) 7.13 (s, 1 H) 7.46 (d, J=9.54 Hz, 1 H) 7.86 (d, J=6.02 Hz, 1 H). 13C NMR (101 MHz, Chloroform-d) δ ppm 15.74, 37.62, 48.39, 49.09, 105.64, 105.90, 123.48, 128.03, 129.65, 129.74, 138.18, 138.63, 141.27, 149.19, 152.43, 155.53, 159.78.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCC[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C([O-])([O-])=O.[K+].[K+]>CCN(CC)CC.CN(C=O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:16][CH2:17][N:18]3[C:22](=[O:23])[C:21]4=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]4[C:19]3=[O:28])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2ccccc2)CC1
Yield: 95 %

Procedure:
1-Phenylpiperazine 2 (2.21 g, 7.81 mmol) was reacted with N-(4-bromobutyl)phthalimide (1.26 g, 7.81 mmol) in the presence of K2CO3 (8.0 g) in Et3N (1.0 mL) and DMF (20 mL) to give a yellow solid 3a, 2.70 (95%) (Procedure A). 1H NMR (CDCl3) 1.55-1.82 (m, 4H, CH2CH2), 2.40-2.45 (t, J=7.5 Hz, 2H, NCH2), 2.57-2.61 (t, J=4.8 HZ, 4H, N(CH2)2), 3.17-3.20 (t, J=4.8 Hz, 4H, N(CH2)2), 3.71-3.75 (t, J=6.7 Hz, 2H, NCH2), 6.82-6.94 (3H, Ar—H), 7.23-7.28 (m, 2H, Ar—H), 7.70-7.74 (m, 2H, Ar—H), 7.83-7.86 (m, 2H, Ar—H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([CH2:12][OH:13])[N:6]3[C:14]4[CH:15]=[CH:16][CH:17]=[C:18]([F:21])[C:19]=4[CH:20]=[C:5]3[C:4]=2[N:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[CH3:22][S:23]([O:13][CH2:12][CH:7]1[N:6]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([F:21])[C:19]=3[CH:20]=[C:5]2[C:4]2[N:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[CH2:8]1)(=[O:25])=[O:24]
Reactant: OCC1Cc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC1Cc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: 0 °C
Yield: 79.6 %

Procedure:
A mixture of (2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-6-yl)methanol (200 mg, 0.66 mmol) and TEA (200 mg, 1.98 mmol) in THF (8 mL) was stirred at 0° C. and MsCl (114 mg, 0.99 mmol) was added dropwise. The reaction was stirred at RT for 8 h. The reaction was washed with 1N HCl and extracted with DCM, dried with Na2SO4 and concentrated to give (2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-6-yl)methyl methanesulfonate (200 mg, yield: 80%). 1H-NMR (CDCl3, 400 MHz) δ 7.54 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.11˜7.20 (m, 3H), 6.79˜6.83 (m, 1H), 5.03˜5.08 (m, 1H), 4.06˜4.21 (m, 2H), 3.46˜3.52 (m, 1H), 3.24˜3.28 (m, 1H), 2.69 (s, 3H). MS (M+H)+: 381/383.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:25][CH2:26][CH2:27][OH:28])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCBr
Reactant: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCCCO)ccc12

Procedure:
1.2 g (3.88 mmol) of 4 are refluxed overnight in 30 ml of acetone together with 0.66 ml (7.6 mmol) of 3-bromo-1-propanol and 2.1 g (15.2 mmol) of potassium carbonate. After cooling, the insoluble residue is filtered off, and the filtrate is evaporated. The crude product can be purified by chromatography on silica gel (eluent gradient toluene/acetone 9:1→4:1), giving ethyl 3-phenyl-3-[6-(3-hydroxypropoxy)indol-3-yl]propionate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].Cl.[O:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:10]1[CH2:14][CH2:13][N:12]=[C:11]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])=[CH:17][CH:16]=1
Reactant: N#CCCCCCBr
Reactant: Oc1ccc(-c2ncco2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCCCOc1ccc(C2=NCCO2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
A mixture of 6-bromohexanenitrile, 12 parts of 4-(2-oxazolyl)phenol monohydrochloride, 16.6 parts of potassium carbonate and 282 parts of N,N-dimethylformamide was stirred overnight at 60° C. After cooling, the reaction mixture was poured into water and the product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.2 parts (20.6%) of 6-[4-(4,5-dihydro-2-oxazolyl)phenoxy]hexanenitrile (int. 107).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:26])=[O:25])=[CH:20][CH:19]=1.[H-].[Li+]>O1CCCC1.C(OC)(C)(C)C>[F:1][C:2]([F:15])([F:16])[C:3]([OH:4])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=1)[CH2:26][C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=1)=[O:25]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: O=C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)CC(O)(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1
Yield: 97.2 %

Procedure:
A solution of 2,2,2-trifluoro-1-[3-(trifluoromethyl)-phenyl]ethanone (3.0 g), 4-methylacetophenone (1.1 g) and lithium hydride (0.13 g) in tetrahydrofuran (30 mL) was stirred for 3 hours at 60° C. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to yield 4,4,4-trifluoro-3-hydroxy-1-(4-methylphenyl)-3-[3-(trifluoromethyl)phenyl]butan-1-one (3.0 g).
Reaction SMILES: C([O-])C.[Na+].C(O)C.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[C:15]([NH2:17])=[NH:16].C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25]CC)=O)C>O>[CH2:31]([O:30][C:28]([C:22]1[C:23]([OH:25])=[N:16][C:15]([C:10]2[N:11]=[CH:12][CH:13]=[CH:14][N:9]=2)=[N:17][CH:21]=1)=[O:29])[CH3:32]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)c1ncccn1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ncccn2)nc1O
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a fresh prepared solution of sodiumethanolate in ethanol (prepared from 0.44 g (18.92 mmol) Na in 20 ml Ethanol) 1.50 g (9.46 mmol) pyrimidine-2-carboxamidine hydrochloride was added. After 10 min. 1.89 ml (9.46 mmol) diethyl ethoxymethylenemalonate was added at 0° and the resulting suspension was stirred for 12 hrs. After addition of 20 ml H2O, the pH was adjusted to 5 and the aqueous phase was extracted three times with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated. The residue was triturated with 5 ml diisopropylether, filtered off and dried to give 1.62 g (70%) 4-hydroxy-[2,2′]bipyrimidinyl-5-carboxylic acid ethyl ester as a light yellow powder, MS (EI): 246.1 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[S:14].O>CN(C=O)C>[N:1]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)=[C:13]=[S:14]
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(N=C=S)cc2N1
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
A solution of 7-amino-3,4-dihydroquinolin-2(1H)-one (0.20 g, 1.2 mmol) in DMF (5.2 mL) was added dropwise to a solution of 1,1′-thiocarbonyldiimidazole (0.22 g, 1.2 mmol) in DMF (2.1 mL) at room temperature over 1 hour. The mixture was stirred for 30 minutes and then water was slowly added. The resulting precipitate was collected by filtration (rinsed with water) and dried under vacuum to afford the title compound (0.21 g, 83% yield), which was used without purification.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:5]=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C>[Br:1][C:2]1[N:3]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:22][CH:23]=2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:5]=2
Reactant: CCCCOc1nc(N)c2nc(Br)n(Cc3ccc(O)cc3)c2n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(Br)n(Cc3ccc(OCC(=O)OCC)cc3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.3 %

Procedure:
8-Bromo-2-butoxy-9-(4-acetoxybenzyl)adenine (0.29 g, 0.67 mmol) obtained in accordance with the method of Reference example 4 was added to methanol (10 ml) and 5% sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature for 4 hours. After the mixture was neutralized with concentrated hydrochloric acid, the resulting solid was filtered and washed with methanol to give 8-bromo-2-butoxy-9-(4-hydroxybenzyl)adenine (0.19 g, 0.49 mmol, yield: 73%) as a white solid. Thus obtained 8-bromo-2-butoxy-9-(4-hydroxybenzyl)adenine (0.05 g, 0.13 mmol) and potassium carbonate (0.02 g, 0.14 mmol) were added to DMF (10 ml), and then thereto was added ethyl bromoacetate (0.04 g, 0.24 mmol). The mixture was stirred at room temperature for 18 hours. After removing the solvent, the residue was poured into water and extracted with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=100/1˜50/1) to give 8-bromo-2-butoxy-9-(4-ethoxycarbonylmethoxybenzyl)adenine (0.06 g, 0.12 mmol, yield: 96%) as a white solid. And then the captioned compound was obtained in accordance with the method of Example 1, Yield: 80%.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([Cl:12])=[CH:7][C:8]=1[C:9]([NH2:11])=[O:10])[NH2:2].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:12][C:6]1[CH:7]=[C:8]([C:9]([NH2:11])=[O:10])[C:3]2[N:4]([N:13]=[N:2][N:1]=2)[N:5]=1
Reactant: NNc1nnc(Cl)cc1C(N)=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)c1cc(Cl)nn2nnnc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To an ice-cold solution of 3-hydrazino-4-aminocarbonyl-6-chloro-pyridazine (4.2 g; 0.0244 mole) [obtained as reported in J. Het. Chemistry, 7, 465 (1970)] in 15% acetic acid, a solution of sodium nitrite (1.55 g) in water (10 ml) was added dropwise. After stirring for one hour at 5°-10° C., the separated precipitate was filtered, crystallized from water, filtered again and dried under vacuum at 50° C. to give 3.44 g (77.5%) of the title compound, m.p. 226° C. (dec.).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:10]([NH:12][C@@H:13]([C:26]([NH:28][C@H:29]([C:37]([N:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]=[O:25])[CH:16]=1)=[O:11])[C@@H:7]([CH3:9])[OH:8])=[O:4].C(O)C>[Pd].C(O)(=O)C>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:10]([NH:12][C@@H:13]([C:26]([NH:28][C@H:29]([C:37]([N:39]([CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]=[O:25])[CH:16]=1)=[O:11])[C@@H:7]([CH3:9])[OH:8])=[O:4]
Reactant: C[C@@H](O)[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H](NC(=O)CN)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1

Procedure:
A solution of Z-Gly-Thr-D-Trp(CHO)-Phe-NMeBzl (560 mg) in a mixed solvent of ethanol (30 ml) and acetic acid (10 ml) was hydrogenated over 10% palladium on carbon (350 mg) under atmospheric pressure for two hours. After filtration of the catalyst and evaporation, the residue was dissolved in water (50 ml) and lyophilized to give H-Gly-Thr-D-Trp(CHO)-Phe-NMeBzl.AcOH (230 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:16]=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:3][CH2:2]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:33]3[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=3)=[N:26][C:27]3[N:28]([CH:30]=[CH:31][N:32]=3)[CH:29]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:25]([C:33]3[CH:40]=[CH:39][C:36]([CH2:37][N:1]4[CH2:2][CH2:3][CH:4]([C:7]5[CH:16]=[N:15][C:14]6[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=6)[N:8]=5)[CH2:5][CH2:6]4)=[CH:35][CH:34]=3)=[N:26][C:27]3[N:28]([CH:30]=[CH:31][N:32]=3)[CH:29]=2)=[CH:22][CH:23]=1
Reactant: c1ccc2nc(C3CCNCC3)cnc2c1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccc(F)cc2)cc1
Product: Fc1ccc(-c2cn3ccnc3nc2-c2ccc(CN3CCC(c4cnc5ccccc5n4)CC3)cc2)cc1

Procedure:
The compound is prepared in analogy to example 33.0. 216 mg (0.756 mmol) 2-Piperidine-4-ylquinoxaline are reacted with 200 mg (0.63 mmol) 4-[6-(4-fluorophenyl)-imidazo[1,2-a]pyrimidin-7-yl]-benzaldehyde. After the usual work-up and purification 201 mg (58.9%) of the title compound are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH:15]([N:18]=[C:19]=[O:20])([CH3:17])[CH3:16]>>[CH:15]([NH:18][C:19]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:3][CH2:2]1)=[O:20])([CH3:17])[CH3:16]
Reactant: CC(C)N=C=O
Reactant: Nc1ccc(CC2CCNCC2)cc1
Product: CC(C)NC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A solution of 4-(piperidin-4-ylmethyl)-phenylamine (0.57 g, 3 mmol) in dicholoromethane (20 mL) was cooled in an ice bath under nitrogen atmosphere. Isopropyl isocyanate (0.28 g, 3.3 mmol) was added dropwise to the solution and stirred at ice bath temperature for 30 minutes. The reaction mixture was quenched with water and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried, and solvents removed in vacuo. The crude product was chromatographed on silica gel, eluting with 2% methanovdichloromethane containing 0.01% ammonium hydroxide, to give 4-(1-isopropylaminocarbonylpiperidin-4-ylmethyl)-phenylamine (0.66 g, 80%) as a gum.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8].[Cl:11][C:12]1[CH:17]=[C:16]([CH:18]=[O:19])[C:15]([F:20])=[CH:14][N:13]=1.[NH4+].[Cl-]>C1COCC1.O>[Cl:11][C:12]1[CH:17]=[C:16]([CH:18]([OH:19])[CH2:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:15]([F:20])=[CH:14][N:13]=1
Reactant: O=Cc1cc(Cl)ncc1F
Reactant: COC(CCBr)OC
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COC(CCC(O)c1cc(Cl)ncc1F)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.5 %

Procedure:
To a solution of Mg (0.71 g, 30 mmol) in THF (10 mL) are added cat iodine and a solution of 3-bromo-1,1-dimethoxy-propane (3.99 g, 21.57 mmol) in THF (10 mL). The mixture is stirred at room temperature for 2 hours. At −30° C., to a solution of 2-chloro-5-fluoro-pyridine-4-carbaldehyde (2.0 g, 12.54 mmol) in THF (5 mL) is added to the above prepared Grignard reagent. The mixture is stirred at this temperature for 2 hours. Then the reaction mixture is cooled in an ice bath, saturated NH4Cl and water are added and the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by chromatography (EtOAc/hexane: 10%˜40%) to give 1-(2-chloro-5-fluoro-pyridin-4-yl)-4,4-dimethoxy-butan-1-ol (0.81 g, 25%). M/Z=264.13[M+1]
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:23]2[CH:24]=[C:19]([CH3:18])[CH:20]=[CH:21][CH:22]=2)[CH:5]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)c1
Yield: 10 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3-methylphenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (16 mg, 10%) which was obtained as a white solid. MS (ESI): m/e=315.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C1C(=O)N([Br:21])C(=O)C1.C(=O)([O-])[O-].[Na+].[Na+]>>[Br:21][C:11]1[S:10][C:9]([C:7]2[S:8][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1ccc(-c2cccs2)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCc1ccc(-c2ccc(Br)s2)s1
Temperature: 0 °C

Procedure:
Next, 8 g (0.038 mol, 1 eq) of the obtained 5-propyl-2,2′-bithiophene was introduced into a three-necked flask, and this was flushed with Ar. To this, 100 ml of THF was added, stirred and cooled to 0° C. To this, 7.4 g (0.042 mol, 1.1 eq) of NBS was added directly. Then, the temperature was returned to the room temperature, and stirred for 12 hours. To this, 10% sodium carbonate aqueous solution was added, this was extracted with diethyl ether, water washed until pH is 7, and dehydrated with Na2SO4. After removing Na2SO4 by filtration, the solvent was removed. This was purified by silica gel chromatography, and specified substance of 5-bromo-5′-propyl-2,2′-bithiophene (3 in the chemical reaction formula) was obtained. Yielding quantity was around 8.8 g, and yielding percentage was around 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C@@H:10]1([NH2:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:20][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(Cl)c1
Product: Clc1cccc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3-Chlorobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[Cl:7][C:8]([Cl:14])=[C:9]([Cl:13])[C:10]([NH2:12])=[O:11]>ClC(Cl)C>[Cl:13][C:9](=[C:8]([Cl:14])[Cl:7])[C:10]([N:12]=[C:2]=[O:3])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)C(Cl)=C(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=C=NC(=O)C(Cl)=C(Cl)Cl
Temperature: 2 °C
Reaction time: 1 h

Procedure:
260 ml of oxalyl chloride were added to 225 g of trichloroacrylamide in 525 ml of dichloroethane cooled to 2° C and the mixture was held at 0° C for 1 hour and then refluxed for 16 hours. The resulting solution was evaporated under reduced pressure and the residue was distilled to obtain 232 g of trichloroacryloyl-isocyanate boiling at 86° C under 20 mm Hg and having a refractive index nD23 = 1.538.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](O)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]1[O:22][C@@H:21]1[CH2:23]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O>>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:23][C@@H:21]2[O:22][CH2:20]2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Oc1cnn(Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(Cn2cc(C[C@H]3CO3)cn2)cc1
Yield: 73.1 %

Procedure:
1-Benzyl-4-hydroxypyrazole (2 g, 11.5 mmol), potassium carbonate(3.2 g, 23 mmol), and (2s)-glycidyl-3-nitrobenzenesulfonate (2.98 g, 11.5 mmol) were slurried in actone (300 ml) at reflux for 17 hours. The acetone was removed in vacuo, the residue extracted from brine with chloroform, and dried over sodium sulfate. The solvent was removed again and the residue purified by column chromatography (silica gel, chloroform→1% methanol/chloroform) to yield product (1.8 g, 68%). MS, NMR.