Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[N:32]=[CH:31][N:30](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:29]=5)[CH:26]=4)[N:21](C4CCCCO4)[N:20]=3)[CH:14]=2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:29]1[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[C:15]2[CH:14]=[C:13]([C:11]([NH:10][C@H:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)=[O:12])[CH:18]=[CH:17][CH:16]=2)=[N:32][CH:31]=[N:30]1
Reactant: O=C(N[C@@H]1CCc2ccccc21)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(N[C@@H]1CCc2ccccc21)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 60 °C
Yield: 9.1 %

Procedure:
To a stirred solution of N-((1R)indanyl)(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.292 g, 0.391 mmol) was added dioxane (4.0 mL) and aqueous 6 N hydrochloric acid (4.0 mL) and the mixture heated at 60° C. for 18 h. The mixture was cooled and poured into saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate phase was pipetted off. The crystals were filtered. Purification by preparative HPLC (30–80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0150 g, 9% yield). 1H NMR (CD3OD) δ 8.80 (s, 1H), 8.55 (s, 1H), 8.23 (d, 1H), 8.13 (d, 1H), 7.96 (dd, 1H), 7.70 (m, 2H), 7.36 (m, 1H), 7.28 (m, 1H), 7.23 (m, 2H), 5.67 (t, 1H), 3.08 (m, 1H), 2.92 (m, 1H), 2.60 (m, 2H), 2.08 (m, 1H). ES-MS (m/z) 421 [M+1]+
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH2:20]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH2:21][CH3:22].N12CCCN=C1CCCCC2>C(#N)C>[CH2:20]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:26]1)[CH2:21][CH3:22]
Reactant: CCCNCC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCNCC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74 %

Procedure:
A suspension of 1.13 g (4.0 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.63 g (4.4 mmole) of 3-[(propylamino]methyl]pyrrolidine, 1.22 g (8.0 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 30 ml of acetonitrile was stirred at room temperature for 2.5 hours. The precipitate was removed by filtration, washed with acetonitrile and dried in vacuo to give 1.15 g (74%) of the title compound, mp 230°-233° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.C(N(CC)CC)C.Cl[CH2:25][CH2:26][N:27]=[C:28]=[O:29].CC(C)([O-])C.[K+]>C1COCC1.O>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:15]=[CH:14][C:12]([N:13]3[CH2:25][CH2:26][NH:27][C:28]3=[O:29])=[CH:11][CH:10]=2)[O:5]1
Reactant: O=C=NCCCl
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(N3CCNC3=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.05 g) and triethylamine (1.34 mL) in THF (20 mL) was added 1-chloro-2-isocyanatoethane (0.409 mL) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a powder. A mixture of the obtained powder and potassium tert-butoxide (1.08 g) in THF (20 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate and diisopropyl ether to give the title compound (0.98 g).
Reaction SMILES: [CH2:1]([C:3](=[CH:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[OH-].[Na+].[CH:13]([Cl:16])(Cl)[Cl:14].O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[Cl:14][C:13]1([Cl:16])[CH:1]([CH3:2])[C:3]1([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC=C(CC)C(=O)OCC
Reactant: ClC(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1(CC)C(C)C1(Cl)Cl
Temperature: 40 °C
Reaction time: 14 h
Yield: 43 %

Procedure:
38 g (0.27 mol) of ethyl 2-ethylbut-2-enoate, 2.2 g (0.01 mol) of benzyltriethylammonium chloride and 57 ml of 50% strength aqueous sodium hydroxide solution were initially charged in 180 ml of dichloromethane. At 35° C. -40° C., 95 ml of chloroform were added dropwise over a period of 1 hour. After a reaction time of 5 hours at 40° C., the mixture was stirred at room temperature for a further 14 hours. For work-up, the reaction solution was poured into 1.5 l of water. The organic phase was removed and the aqueous phase was then extracted with dichloromethane. The combined organic phases were washed with water and, after drying with magnesium sulfate, concentrated. The residue (47 g) was subjected to vacuum distillation. The title compound was isolated as a colorless liquid (25.7 g, 43% yield, boiling point 71° C. at 2 mbar).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][C:4]1([CH3:10])[CH3:9].[Cl:11]OC(C)(C)C>CO>[Cl:11][N:5]1[C:4]([CH3:10])([CH3:9])[CH:3]([CH2:2][OH:1])[O:7][C:6]1=[O:8]
Reactant: CC1(C)NC(=O)OC1CO
Reactant: CC(C)(C)OCl
Solvent: CO
Product: CC1(C)C(CO)OC(=O)N1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a 0° C. solution of 5-(hydroxymethyl)-4,4-dimethyloxazolidin-2-one (250 mg, 1.72 mmol) in 2 mL of methanol was added tertbutyl hypochlorite (290 uL, 2.58 mmol). The reaction was stirred at 0° C. for 1 hour, then concentrated to a crude residue under reduced pressure. The crude product was purified by column chromatography (20 to 80% ethyl acetate in hexanes) to give the title compound as a clear liquid (248 mg, 1.38 mmol, 80%). 1H NMR (CDCl3, 400 MHz) δ 1.29 (s, 3H), 1.42 (s, 3H), 2.28-2.31 (dd, J=4.8, 7.7 1H), 3.85-3.88 (m, 1H), 3.91-3.98 (m, 1H), 4.37-4.40 (dd, J=4.7 6.9 Hz, 1H). LRMS (ESI/APCI) m/z 180 [M+H]+.
Reaction SMILES: B.[O:2]1CCCC1.[C:7]([O:11][C:12](=[O:19])[NH:13][CH:14]1[CH2:18][CH:17]=[CH:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:19])[NH:13][C@H:14]1[CH2:15][CH2:16][C@@H:17]([OH:2])[CH2:18]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NC1CC=CC1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of cyclopent-3-enecarboxylic acid (2.25 g), diphenylphosphoryl azide (4.7 mL), and triethylamine (2.8 mL) in 25 mL toluene was refluxed for 7 h. The mixture was cooled to rt and treated with 10 mL of tert-butanol. The resulting mixture was refluxed for an additional 16 h. The solvents were evaporated and the crude residue was chromatographed with silica gel (1:10 ethyl acetate:hexanes) to give Cyclopent-3-enylcarbamic acid tert-butyl ester (racemic): (2.37 g). Borane-tetrahydrofuran (1.5 M in THF, 20 mL) was added dropwise to a solution of cyclopent-3-enylcarbamic acid tert-butyl ester (1.83 g) in tetrahydrofuran (30 mL) at 0° C. The solution was gradually warmed to rt and stirred for 16 h. The reaction solution was cooled to 0° C. and sodium hydroxide (1 N, 33 mL) was slowly added followed by 30% hydrogen peroxide (33 mL). The resulting mixture was stirred at rt for an additional 5 h and diluted with ethyl acetate (70 mL). The aqueous layer was separated and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated via rotary evaporator. Silica gel chromatography (1:1 ethyl acetate:hexanes) provided 0.25 g of cis-(3-hydroxycyclopentyl)carbamic acid tert-butyl ester (racemic) followed by 1.07 g of the trans isomer. A solution of cis-(3-hydroxycyclopentyl)-carbamic acid tert-butyl ester (201 mg) in dimethylformamide (3 mL) was treated with sodium hydride (60% in mineral oil, 95 mg) at 0° C. After gas evolution had ceased, the mixture was stirred for 30 min at rt. Iodoethane (88 μL) was added to the mixture and the reaction was stirred at rt for 16 h. The excess sodium hydride was destroyed at 0° C. by the careful addition of aqueous ammonium chloride. The resulting mixture was partitioned between ethyl acetate and ammonium chloride and the organic layer was separated and washed with brine. The organic layer was dried over Na2SO4 and concentrated via rotary evaporator. Silica gel chromatography (1:4 ethyl acetate:hexanes) provided cis-(3-ethoxycyclopentyl)carbamic acid tert-butyl ester (racemic) (102 mg). Cis-(3-ethoxycyclopentyl)carbamic acid tert-butyl ester was stirred in 1:1 trifluoroacetic acid:dichloromethane for 0.5 h. The solvent was removed by evaporation to provide cis-3-ethoxycyclopentylamine (racemic).
Reaction SMILES: [CH:1]([OH:14])([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.CC(C)([O-])C.[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH2:40]Cl)[CH2:35][CH2:34]2)=[CH:24][CH:23]=1>C(O)(C)(C)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][O:14][CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:35][CH2:34]2)=[CH:24][CH:23]=1
Reactant: Fc1ccc(C(OCCCN2CCN(CCCl)CC2)c2ccccc2)cc1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Fc1ccc(C(OCCCN2CCN(CCOC(c3ccccc3)c3ccccc3)CC2)c2ccccc2)cc1

Procedure:
10.1 g of benzhydrol are refluxed with 6.2 g of potassium tertiary butoxide in 100 ml of anhydrous tertiary butanol under argon gas for 30 minutes, then 19.6 g of 1-[3-[(4-fluorophenyl)-phenylmethoxy]propyl]-4-(2-chloroethyl)piperazine dissolved in 40 ml of anhydrous tertiary butanol are dropwise added. The mixture is boiled for one additional hour, then evaporated to about 40 ml under reduced pressure and after adding water it is extracted with benzene. The organic phase is dried over anhydrous magnesium sulfate and, after evaporating benzene under reduced pressure, the residue is fractionally distilled. The aimed compound boils at 247°-250° C./0.01 Hgmm.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([Cl:12])[CH:3]=1.[CH:13](OCC)(OCC)OCC>>[Cl:11][C:6]1[C:7]2[C:8](=[O:9])[NH:10][CH:13]=[N:1][C:2]=2[CH:3]=[C:4]([Cl:12])[N:5]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1c(N)cc(Cl)nc1Cl
Product: O=c1[nH]cnc2cc(Cl)nc(Cl)c12
Temperature: 150 °C

Procedure:
A mixture of 4-Amino-2,6-dichloronicotinamide (9.0 g, 43.7 mmol) and triethyl orthoformate (90 mL) was heated at 150° C. in a ChemGlass bomb for 6 hours and evaporated under reduced pressure to afford the title compound. 1H NMR (DMSO-d6) δ 7.72 (s, 1H), 8.31 (1H); ESI-MS m/z 216.0 (MH+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.CN([CH:28]=[O:29])C>>[CH2:6]([N:13]1[C:19]2[CH:20]=[CH:21][C:22]([CH:28]=[O:29])=[CH:23][C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1=Cc2ccccc2N(Cc2ccccc2)C=C1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc2c(c1)C=CC=CN2Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (1.9 ml, 20.4 retool) was added to DMF (10 ml) at ambient temperature and the mixture was stirred for 30 minutes under nitrogen atmosphere. To the mixture was added crude 1-benzyl-1H-1-benzazepine (3.23 g, 13.6 mmol) in DMF (5 ml) at ambient temperature. The mixture was stirred at ambient temperature for 1 hour and at 70° C. for 2 hours. Water (35 ml) was added and the mixture was stirred for 10 minutes. The mixture was extracted with EtOAc (2×100 ml) and the combined extracts were washed with H2O (2×50 ml), saturated NaHCO3 solution (50 ml) and brine (50 ml). The solution was dried over MgSO4 and concentrated in vacuo affording the title compound as a brown oil (3.42 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:54][C:55](=[N:61]O)[C:56]([O:58][CH2:59][CH3:60])=[O:57]>O1CCOCC1>[NH2:61]/[C:55](=[N:54]\[O:10][C:9]([C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])=[O:11])/[C:56]([O:58][CH2:59][CH3:60])=[O:57]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: CCOC(=O)C(N)=NO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)/C(N)=N/OC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A solution of (2R)-2-[2-(tert-Butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 175) (7.53 g, 25.2 mmol) in 1,4-dioxane (175 ml) was treated with 1-hydroxybenzotriazole hydrate (3.75 g, 27.8 mmol) and the mixture cooled to 0° C. N,N′-Dicyclohexylcarbodiimide (5.47 g, 26.5 mmol) was then added and the mixture was stirred for 3 hours being allowed to warn to room temperature over this time. The mixture was then filtered and washed with 1,4-dioxane (2×50 ml). The filtrate was then treated with sodium carbonate (4.01 g, 37.8 mmol) and ethyl 2-amino-2-(hydroxyimino)acetate (J. Org. Chem.;23; 1958; 1794) (3.33 g, 25.2 mmol). The resulting mixture was stirred at room temperature for 17 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous phase was extracted with ethyl acetate (×2). The combined organic layers were dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate:pentane (30:70) gradually changing to ethyl acetate:pentane (50:50) to afford the title compound as a white solid (6.50 g).
Reaction SMILES: Cl[CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].Cl.[Cl:12][C:13]1[CH:14]=[N:15][C:16](=[O:19])[NH:17][CH:18]=1>ClCCl>[O:4]([CH:2]([N:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[N:15][C:16]1=[O:19])[CH3:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(Cl)Oc1ccccc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: ClCCl
Product: CC(Oc1ccccc1)n1cc(Cl)cnc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in a manner similar to that described in Example 6 by adding a solution of α-chloroethoxybenzene [see Preparation 8] (4.5 mmol) in dichloromethane (5 ml) to a solution from 5-chloropyrimidin-2-one hydrochloride (4.5 mmol) in dichloromethane (15 ml) at 5° C., and the mixture was stirred at room temperature for 2 h before being worked up. The product was a mixture of the desired N-isomer and the O-isomer in the ratio 3:2; yield 0.85 g (76%). The isomers were separated by chromatography on silica gel using chloroform as above; m.p. 92° C. (CH2Cl2 /Pet.ether). (Found: C58.02; H 4.51 Calc. for C12H11ClN2O2 : C57.49; H4.43) 1H NMR (CDCl3): δ 1.72 (Me, d, J 5Hz), 6.4-7.3 (Ph,H-α), 7.79 and 8.40 (H-4 and H-6, respectively, J 3 Hz). IR (KBr): 1665 cm-1 (CO). MS [70 eV, m/z (% rel. int.)]: 250 (l,M), 159 (30)), 157 (100), 121 (23), 77 (30), 65 (17).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]([C:18]1([C@H:21]2[CH2:25][N:24]([C@H:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:27])[C:23](=[O:34])[CH2:22]2)[CH2:20][CH2:19]1)=[O:17])[CH3:14].[O:35]=O.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:13]([O:15][C:16]([C:18]1([C@H:21]2[CH2:25][N:24]([C@H:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH3:27])[C:23](=[O:34])[C@@H:22]2[OH:35])[CH2:19][CH2:20]1)=[O:17])[CH3:14]
Reactant: O=O
Reactant: CCOC(=O)C1([C@@H]2CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@@H]2O)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
Under a nitrogen atmosphere, diisopropylamine (3.93 ml, 28.0 mmol) was dissolved in anhydrous tetrahydrofuran (200 ml) to which, after cooling to −78° C., was subsequently added dropwise an n-hexane solution of 1.69 M n-butyl lithium (15.9 ml, 26.9 mmol) over a period of 10 minutes. After 20 minutes of stirring at 0° C. and subsequent cooling to −78° C., to the resulting reaction solution was added dropwise anhydrous tetrahydrofuran solution (40 ml) of 4-(S)-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]-2-pyrrolidone (6.74 9, 22.4 mmol) over a period of 15 minutes. The reaction solution was stirred at −78° C. for 10 minutes and then the reaction vessel was charged with dried oxygen at the same temperature. The reaction solution was stirred at −78° C. for 20 minutes and then mixed with a saturated ammonium chloride aqueous solution (200 ml). This was warmed up to room temperature and the organic layer was separated. The aqueous layer was extracted with diethyl ether (200 ml×2), and the organic layers were combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=2:1, to thereby obtain 5.21 g (73%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH2:18]([C:22](N(OC)C)=[O:23])[CH2:19][CH2:20][CH3:21]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:22](=[O:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CCCCC(=O)N(C)OC
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: CCCCC(=O)c1ccc(OC)cc1C(=O)O

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with butyl-N-methoxy-N-methylcarboxamide. It is used in crude form in the following reaction.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](SC)=[N:18][C:19](=[S:36])[N:20]([CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([O:28]C(C)(C)C)=[O:27])[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=[O:42]>ClCCl>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:42])[NH:18][C:19](=[S:36])[N:20]([CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([OH:28])=[O:27])[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CSc1nc(=S)n(Cc2cccc(C(=O)OC(C)(C)C)c2)cc1C1c2ccccc2C=Cc2ccccc21
Solvent: ClCCl
Product: O=C(O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=S)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of the product from step (vi) (0.5 g) in dichloromethane (12 ml) was treated with trifluoracetic acid (9 ml) and stirred at room temperature for 3.5 hours. The mixture was evaporated and the residue dissolved in ethanol (50 ml) and 2M HCl. The mixture was heated at reflux at 4 hours. The mixture was evaporated and the residue treated with water, filtered and dried (MgSO4). Purified by chromatography eluting with 5% methanol in dichloromethane. Yield 0.27 g.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27]2[CH:28]=[N:29][C:30]3[C:35]([C:36]=2[NH2:37])=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:27]3[CH:28]=[N:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=4[C:36]=3[NH:37][C:1]2=[O:2])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1c(NC2CCN(Cc3ccccc3)CC2)cnc2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2c3ccccc3ncc2n1C1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
22.6 g (139 mmol) 1,1′-carbonyldiimidazole were added to 9.00 g (27.1 mmol) N3-(1-benzylpiperidin-4-yl)-quinoline-3,4-diamine in 100 mL DMF. The mixture was heated to 100° C. and stirred for 1.5 h. After the reaction mixture had cooled it was poured onto 300 mL water. The precipitated solid was filtered off, washed with water and dried i. vac. At 30° C. The residue was triturated with diethyl ether, suction filtered and the solid product was dried i. vac.
Reaction SMILES: [C:1]12([CH:11](I)[C:12]([OH:14])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:16][NH2:17]>O1CCCC1>[C:1]12([CH:11]([NH:17][CH3:16])[C:12]([OH:14])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CN
Reactant: O=C(O)C(I)C12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Product: CNC(C(=O)O)C12CC3CC(CC(C3)C1)C2

Procedure:
Adamantan-1-yl-iodo-acetic acid (7.86 g, 24.55 mmol, P. A. Krasutskii. et. Al. J. Org. Chem. USSR (Engl. Trans.); 1985; 1327-1332) is refluxed with 100 mL of 2M methylamine in tetrahydrofuran for 18 hours. The solvent is evaporated in vacuo, and the residue treated with water. The pH is adjusted to 6 and the resulting solid collected and dried to give 2.16 g of the title compound as a white solid. MS: m/z 224.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][N:5]=[N+:6]=[N-:7].[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=O)[S:13][CH:14]=1.C[O-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:8])[C:4]([N:5]=[N+:6]=[N-:7])=[CH:15][C:12]1[S:13][CH:14]=[C:10]([Br:9])[CH:11]=1
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: O=Cc1cc(Br)cs1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=Cc1cc(Br)cs1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a solution of azido-acetic acid methyl ester (25 g, 220 mmol) and 15 g of 4-bromo-thiophene-2-carbaldehyde (14.0 g, 73 mmol) in 50 ml of MeOH cooled at −25° C. was added a solution NaOMe in MeOH (51 ml, 4.36 M). The resulting mixture (slush) was stirred with a mechanical stirrer for 2 h at 0° C. and the 200 g of ice was added. The yellow solid was collected by filtration and air-dried to give 15 g of the title product which was used for the next step without further purification.