Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][CH2:11][S:10]1(=[O:18])=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:19][CH:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:21]([OH:25])[C:22]([NH2:24])=[O:23].O[NH-].O=[N-]>>[NH2:24][C:22](=[O:23])[C:21](=[O:25])[CH:20]([NH:19][C:14]([CH:13]1[CH2:12][CH2:11][S:10](=[O:18])(=[O:17])[N:9]1[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:16])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)C1CCS(=O)(=O)N1Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Agent: [Na]
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)C1CCS(=O)(=O)N1Cc1ccccc1

Procedure:
Coupling of the sodium salt of 2-benzyl-1,1-dioxo-isothiazolidine-3-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: C(O[C:6](=[O:19])[NH:7][C@@H:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:9]([OH:11])[CH3:10])(C)(C)C.[H-].[Na+].Br[CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[C:37]([F:43])=[CH:36][C:35]=1[O:44][CH3:45]>>[CH2:12]([C@H:8]1[C@@H:9]([CH3:10])[O:11][C:6](=[O:19])[N:7]1[CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[C:37]([F:43])=[CH:36][C:35]=1[O:44][CH3:45])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Reactant: C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](C)[C@@H]1Cc1ccccc1

Procedure:
tert-butyl[(1S,2S)-1-benzyl-2-hydroxypropyl]carbamate (Example 317, Step B, 39 mg, 0.148 mmol) was treated with sodium hydride (60% in oil, 12 mg, 0.309 mmol) and 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (Intermediate 10, 50 mg, 0.123 mmol) as described in Example 305 to afford (4S,5R)-4-benzyl-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-one as a clear glass. LCMS=516.4 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.64-759 (m, 2H), 7.33-7.30 (m, 1H), 7.28-7.21 (m, 2H), 7.16 (s, 1H), 7.00-6.91 (m, 3H), 6.67 (d, J=3 Hz, 1H), 4.70 (d, J=2.7 Hz, 1H), 4.52-4.47 (m, 1H), 3.95 (d, J=15.8 Hz, 1H), 3.70 (s, 3H), 3.68-3.62 (m, 1H), 3.24-3.18 (m, 1H), 2.72-2.53 (m, 2H), 1.28-1.21 (m, 6H), 1.19 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:15]([NH2:16])=[CH:14][C:12](=[O:13])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH2:18][CH2:19]Br.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]1[C:15]([NH2:16])=[CH:14][C:12](=[O:13])[N:11]([CH2:17][CH2:18][CH3:19])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCBr
Reactant: Nc1cc(=O)[nH]c(=O)n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1c(=O)cc(N)n(Cc2ccccc2)c1=O
Yield: 44.6 %

Procedure:
3.0 g (0.014 mol) of 1-benzyl-6-aminouracil are stirred for 3 hours at 70° C. with 2.2 g (0.018 mol) of n-propyl bromide, 4.2 ml of 15% sodium hydroxide solution and 7 ml of ethanol. The mixture is poured onto ice and extracted with methylene chloride. The organic phases are dried and evaporated down. The residual oil is crystallised from a mixture of methylene chloride and methanol. 1.62 g of the title compound are obtained in the form of white crystals (47% of theory), m.p. 189°-192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[NH:12][C:13]([CH2:15][CH3:16])=[N:14][C:6]1=[N:5]2.[O-]CC.[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.O1CCCC1>[CH2:22]([N:12]1[C:7]2=[N:8][C:9]3[C:4]([N:5]=[C:6]2[N:14]=[C:13]1[CH2:15][CH3:16])=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=3)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: CCc1nc2nc3cc(Cl)ccc3nc2[nH]1
Agent: CC[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCn1c(CC)nc2nc3cc(Cl)ccc3nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 75 parts of 6-chloro-2-ethyl-1H-imidazo[4,5-b]quinoxaline, 85 parts of thallous ethoxide, and 600 parts of 2:1 anhydrous dimethylformamide-tetrahydrofuran was stirred at room temperature for 1 hour. Allyl bromide (50 parts) was added in one portion, and the mixture was stirred for an additional hour, followed by heating for 30 minutes on a steam bath. The mixture was filtered, and the filtrate was diluted with 2000 parts of water. The filtrate was extracted with three 500 -part portions of chloroform, and the combined extracts dried (potassium carbonate) and evaporated in vacuo. The residue was dissolved in 500 parts of benzene and decolorized (silica gel). The benzene was removed in vacuo and the crude product recrystallized from 95:5 ether-ethanol to yield 24 parts of 1-allyl-6-chloro-2-ethyl-1H-imidazo[4,5-b]quinoxaline, m.p. 117°-121°.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2cccc(F)c2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 3-fluorophenylboronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless foam (35%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:39][C:40]([F:58])([F:57])[O:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:1][C:2]1[C:3]([C:12]([N:54]2[CH2:53][CH2:52][N:51]([S:48]([C:45]3[CH:46]=[CH:47][C:42]([O:41][C:40]([F:57])([F:58])[F:39])=[CH:43][CH:44]=3)(=[O:49])=[O:50])[CH2:56][CH2:55]2)=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1c(C(=O)O)ccc2cccnc12
Reactant: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)ccc2cccnc12
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
To the solution of 8-methyl-7-quinolinecarboxylic acid (may be prepared as described in Intermediate 2; 90 mg, 0.483 mmol) in N,N-Dimethylformamide (DMF) (2 ml), HATU (193 mg, 0.508 mmol) was added at room temperature. The reaction was stirred for 20 min and then 1-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)piperazine (may be prepared as described in Intermediate 11; 150 mg, 0.483 mmol) was added followed by DIPEA (0.211 ml, 1.209 mmol) and the reaction mixture was stirred for 3 hours. The reaction mixture was poured into the separating funnel and partitioned between ethyl acetate (25 ml) and sodium hydroxide (15 ml). The organic phase was washed with sodium hydroxide (2×10 ml), water (2×10 ml) and brine (10 mL) before it was dried using phase separator and the solvent was removed under vacuum. The crude product was purified by MDAP to give the title compound as a white solid (115 mg).
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[N:11]([O:20][CH3:21])[CH2:12][C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=3[CH:19]=2)C=CC=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:21][O:20][N:11]1[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:22])=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH2:12]1
Reactant: CON1CC2=C(C=C1NC(=O)Oc1ccccc1)CCCC2
Reactant: Clc1cccc(N2CCNCC2)c1
Product: CON1CC2=C(C=C1NC(=O)N1CCN(c3cccc(Cl)c3)CC1)CCCC2
Yield: 69 %

Procedure:
Phenyl-N-(2-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:31][CH2:32][C:33](Cl)=O>ClCCl>[Cl:31][CH2:32][C:33]1[N:19]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2ccccc12
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
Triethylamine (20.4 g, 202 mmol) was added to a solution of tert-butyl 3-[(3-aminoquinolin-4-yl)amino]propylcarbamate (42.52 g, 134.4 mmol) in dichloromethane (500 mnL). Chloroacetyl chloride (16.7 g, 148 mmol) was added dropwise, and the reaction was stirred overnight at ambient temperature. The reaction mixture was filtered to remove a solid; the filtrate was concentrated under reduced pressure and mixed with ethyl acetate. The resulting mixture was filtered to remove a solid, washed sequentially with brine (3×) and dilute aqueous sodium bicarbonate, concentrated under reduced pressure, and dried under high vacuum to provide 41.9 g of tert-butyl 3-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH2:5]2.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:28]([O:30][CH:31]([O:35][CH2:36][CH3:37])[CH:32](Cl)[CH3:33])[CH3:29]>CN(C=O)C.O>[C:16]1([CH2:15][CH2:14][CH2:13][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:33][CH2:32][CH:31]([O:35][CH2:36][CH3:37])[O:30][CH2:28][CH3:29])[CH:3]=3)[C:8]2=[O:12])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1c2ccc(O)cc2CCN1CCCc1ccccc1
Reactant: CCOC(OCC)C(C)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CCOc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O)OCC

Procedure:
A solution of 6-hydroxy-2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline (7.55 g, 26.87 mmol), Cs2CO3 (18 g, 53.74 mmol) and chloropropionaldehyde diethyl acetal (5.4 mL, 32.2 mmol) in DMF (100 mL) is stirred for 48 hours. After this time the reaction is diluted with H2O (400 mL) and the resulting mixture extracted with EtOAc (2×200 mL). The combined organic phases are washed with saturated NaCl solution (2×400 mL), dried over MgSO4 and concentrated in vacuo. The residue is chromatographed (silica gel, 1:9 EtOAc/hexane ) to give 2-(3-phenylpropyl)-6-(3,3-diethoxypropyloxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline which is hydrolyzed with 6N HCl in tetrahydrofuran at room temperature to yield β-[2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy]-propionaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH:11]([C:13]([OH:15])=[O:14])[NH2:12])=[CH:5][CH:4]=1.[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:19]#[C:20][CH3:21]>>[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:12][CH:11]([CH2:10][C:9]2[C:16]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:17]=3)[NH:7][CH:8]=2)[C:13]([OH:15])=[O:14])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:19]#[C:20][CH3:21]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2[nH]cc(CC(N)C(=O)O)c2c1
Product: CC#CCOc1ccc(S(=O)(=O)NC(Cc2c[nH]c3ccc(OC)cc23)C(=O)O)cc1

Procedure:
The title compound was prepared by the method of Example 6, using 5-methoxy-DL-tryptophan and 4-but-2-ynyloxy-benzenesulfonyl chloride as starting materials. 1H NMR (DMSO-d6): 400 MHz δ 12.55 (bs, 1H), 10.63 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.53 (dd, J=8.0, 4.0 Hz, 2H), 7.18 (d, J=8.0 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 2H), 6.82 (d, J=2.0 Hz, 1H), 6.68 (dd, J=8.0, 2.0 Hz, 1H), 4.78 (q, J=2.0 Hz, 2H), 3.87 (q, J=7.6 Hz, 1H), 3.72 (s, 3H), 3.00 (dd J=14.4, 6.4 Hz, 1H), 2.82 (dd J=14.4, 7.6 Hz, 1H), 1.83 (t, J=2.0 Hz, 3H); HRMS: calcd for C22H24N2O6S (ESI+, [M+H]1+), 443.1271; found 443.1265; LCMS m/z (ESI) [M+H] 443, retention time=2.50 min.
Reaction SMILES: [Br:1][C:2]1[C:7](C=O)=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH:14]([O:19][CH3:20])([O:17][CH3:18])OC>CO>[CH3:20][O:19][CH:14]([O:17][CH3:18])[C:7]1[C:2]([Br:1])=[CH:3][C:4]([O:12][CH3:13])=[C:5]([O:10][CH3:11])[CH:6]=1
Reactant: COC(OC)OC
Reactant: COc1cc(Br)c(C=O)cc1OC
Solvent: CO
Product: COc1cc(Br)c(C(OC)OC)cc1OC
Temperature: 25 °C

Procedure:
6-Bromo-3,4-dimethoxybenzaldehyde (470 g) is suspended in methanol (600 ml), and thereto are added trimethyl orthoformate (1025 ml) and IRA-120 (H+ -type, 10 g), and the mixture is refluxed for one hour. The mixture is cooled to room temperature, and the insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in ether, washed, dried, evaporated to remove the ether, and distilled under reduced pressure to give 6-bromo-3,4-dimethoxybenzaldehyde dimethyl acetal (522 g) as a main distillate (133-138° C./1 Torr).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[CH3:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=2)[CH:6]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Br)cnc1N
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cnc1N
Yield: 88.2 %

Procedure:
Prepared as described in example C.32 (step 4) from commercially available 2-amino-5-bromo-3-methyl-pyridine (4.5 g, 24.1 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (5.03 g, 26.5 mmol). Obtained as an off-white solid (5.36 g, 88%). MS (ISP) 252.9 [(M+H)+]; mp 159° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:30]=[N+:31]=[N-:32])(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([C:7]2[N:30]=[N:31][NH:32][N:8]=2)=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1OC
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1cc(-c2nn[nH]n2)c([N+](=O)[O-])cc1OC
Temperature: 100 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
2.33 g of 4,5-dimethoxy-2-nitro-benzonitrile was added to 15 ml of toluene, 0.28 g of dibutyltinoxide and 2.58 g of trimethylsilyl azide was added thereto, and the mixture was stirred at 100° C. for 16 hours. The reaction mixture was distilled under a reduced pressure to remove the solvent, and the resulting solid was washed with 250 ml of dichloromethane to obtain 2.0 g of the title compound as a grey solid (yield 71%).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:10]([OH:12])=[O:11].[CH3:19]O>>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:10]([O:12][CH3:19])=[O:11]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Thionyl chloride (3.7 g) was added dropwise under ice cooling to a solution of 4.7 g (24 mmol) of 3-methoxy-4-nitrobenzoic acid in 250 ml of methanol. The thus-obtained mixture was stirred at room temperature for 2 hours and then stirred under heating and reflux for 3 hours. After the solvent was distilled out under reduced pressure, the residue was neutralized with aqueous ammonia and then extracted with methylene chloride. The extract was dried over sodium sulfate and then dried up under reduced pressure, whereby 4.9 g of white powder were obtained (yield: 97%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C-:11]#[N:12].[Na+]>CC#N.CCOC(C)=O.[Cu]I>[C:11]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)#[N:12]
Reactant: [C-]#N
Reactant: Ic1ccc2[nH]ccc2c1
Agent: [Cu]I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of 5-iodoindole (0.36 g; 1.48 mmol), NaCN (0.15 g; 3 mmol), Pd(Ph3)4 (0.23 g; 0.22 mmol) and CuI (0.06 g; 0.3 mmol) in anhydrous CH3CN (3 ml) was refluxed for 2.5 h under N2. After cooling to room temperature, the mixture was diluted to 20 ml with EtOAc and filtered through a pad of Celite. The filtrate was washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure, dissolved in a small volume of CH2Cl2 and filtered through a small pad of SiO2, which was washed with fresh CH2Cl2. The combined filtrates were evaporated to dryness under reduced pressure to give the title compound (0.2 g; 95%) as colourless solid. 1H-NMR (CDCl3) 6.62 (tr, 1H, J=2.5 Hz); 7.33 (tr, 1H, J=2.5 Hz); 7.39-7.47 (m, 2H); 7.98 (s, 1H); 8.51 (broad s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[C:11]#[N:12])[N:6]=1.N1C=CC=CC=1.[C:25]1([CH2:31][CH2:32][O:33][C:34](Cl)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[C:11](/[C:10](=[N:9]\[O:8][CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:34](=[O:35])[O:33][CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:3][CH:4]=1)/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:12]
Reactant: O=C(Cl)OCCc1ccccc1
Reactant: N#C/C(=N\OCc1csc(N)n1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#C/C(=N\OCc1csc(NC(=O)OCCc2ccccc2)n1)c1ccccc1
Reaction time: 5 h
Yield: 76.3 %

Procedure:
To a solution of (2Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)acetonitrile (1 g, 3.87 mmol, 1 eq.) in dry dichloromethane (15 ml) at room temperature was added pyridine (0.38 ml, 4.65 mmol, 1.2 eq). After stirring for 15 min at room temperature 2-phenylethylcarbonochloridate (858 mg, 4.65 mmol, 1.2 eq) was added and stirring was allowed during 5 h. The reaction was quenched by addition of water and concentrated to dryness. The residue was taken in DCM (5 mL) and 5 ml of 1N NaOH was added. The layers were separated and the organic phase was dried over MgSO4 then concentrated to give 2-phenylethyl {4-[({[(Z)-cyano(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-yl}carbamate (1.2 g, 55% yield) which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26])=[O:4].Br[CH2:28][CH2:29][CH3:30].Cl>CN(C)C=O>[CH:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:28][CH2:29][CH3:30])[CH:9]=[C:8]2[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26])=[O:4]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C=O)cc23)c(OC)c1
Reactant: CCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=O)ccc21
Reaction time: 1 h
Yield: 84.9 %

Procedure:
Sodium hydride (2.96 g of a 60% w/w dispersion in mineral oil) was added to dry dimethylformamide (DMF, 100 ml), under a nitrogen atmosphere. The mixture was stirred and cooled in an ice-bath, and a solution of methyl 4-(5-formylindol-3-ylmethyl)-3-methoxybenzoate (20 g) in DMF (75 ml) added slowly. After 1 h, 1-bromopropane (9.13 g) was added slowly. After 2 h, the mixture was carefully acidified with 2M hydrochloric acid (100 ml), extracted with ethyl acetate (twice), and the extract washed with 1M hydrochloric acid, water, and brine. The dried (MgSO4) solution was evaporated, and the residue dissolved in ethyl acetate and filtered through a pad of silica gel. The filtrate was evaporated, and the product crystallised from ether to give methyl 4-(5-formyl-1-propylindol-3-ylmethyl)-3-methoxybenzoate (19.2 g, 85%) as white needles; mp 98-99°; partial NMR (250 MHz, DMSO-d6): 0.82(t, 3H, CH3), 1.75(m, 2H, CH2), 3.83(s, 3H, OCH3), 3.92(s, 3H, OCH3), 4.1(m, 4H, ArCH2Ar' and NCH2), 9.95(s, 1H, CHO).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CNCCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
In a manner analogous to the method described in examples 8, rac-(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was coupled with 2-piperazinone (Alfa) to give the title compound. HR-MS (ES, m/z) calculated for C33H38Cl2N5O3 [(M+H)+] 622.2346, observed 622.2341.
Reaction SMILES: N.[C:2]([NH2:5])(=[O:4])[CH3:3].[C:6]([O:9][CH2:10][CH2:11]Cl)(=[O:8])[CH3:7]>[NH2-].[Na+]>[C:6]([O:9][CH2:10][CH2:11][NH:5][C:2](=[O:4])[CH3:3])(=[O:8])[CH3:7]
Reactant: CC(=O)OCCCl
Reactant: CC(N)=O
Agent: N
Agent: [NH2-]
Agent: [Na+]
Product: CC(=O)NCCOC(C)=O

Procedure:
To 150 ml of liquid ammonia in which 7.8 g of sodium amide had been dissolved, was added 12 g of acetamide and the reaction mixture was reacted at room temperature for 5 hours in a pressure-resistant reaction tube. Then, 57 g of 2-chloroethyl acetate was added to the reaction solution, followed by a further reaction for 3 hours at room temperature. After the completion of the reaction, ammonia was distilled off and 10% aqueous hydrochloric acid solution was added to the resulting residue so as to obtain an aqueous solution of pH 5. The aqueous solution was extracted twice with 100 ml of ethylacetate. The ethylacetate layers were dried with magnesium sulfate, followed by the distillation-off of ethylacetate. The residual substance was subjected to a distillation under reduced pressure but the intended product, N-acetoxyethylacetamide(138°-140° C./ 2 mmHg) did not come out.