Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C1COCC1>[O:11]=[C:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([NH:1][C:12](=[O:14])[CH3:13])=[CH:3][CH:4]=2)[NH:8]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)NC(=O)C2
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Yield: 65.1 %

Procedure:
To 6-aminoindolin-2-one (30 mg, 0.202 mmol) in THF (1 mL) was added acetic anhydride (19 uL, 0.202 mmol). After 2 hrs the product was precipitated with ether, filtered and dried to give 25 mg, 66% of a white solid. 1H NMR (400 MHz, CD3OD) δ 7.41 (s, 1H), 7.16 (d, J=7.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.49 (s, 2H), 2.12 (s, 3H); MS ESI 191.0 [M+H]+, calcd for [C10H10N2O2+H]+ 191.08.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:12])=[NH:11].[Cl:13][C:14]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:15]=1[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19]>>[NH2:21][CH2:20][C:17]1[C:18]([NH2:19])=[N:11][C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[N:12][C:16]=1[C:15]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:14]=1[Cl:13]
Reactant: N=C(N)c1cc2ccccc2[nH]1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2cc3ccccc3[nH]2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=383.9 (M+H+), was prepared from 1H-indole-2-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:13][C:14]1[N:15]=[CH:16][S:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][C:14]2[N:15]=[CH:16][S:17][CH:18]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClCc1cscn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2cscn2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 60.8 %

Procedure:
A mixture of 4-nitrophenol (3.92 g), 4-chloromethyl-1,3-thiazole hydrochloride (4.0 g), potassium carbonate (8.13 g) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 40 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-[(4-nitrophenoxy)methyl]-1,3-thiazole as colorless crystals (3.38 g, yield 61%). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 175-176° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[C@H:5]([CH3:32])[CH2:6][C@H:7]([NH:21][C:22]([C:24]1[S:25][C:26]([C:29](=[O:31])[NH2:30])=[CH:27][CH:28]=1)=[O:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+]>C(O)C>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([NH:21][C:22]([C:24]2[S:25][C:26]([C:29](=[O:31])[NH2:30])=[CH:27][CH:28]=2)=[O:23])[CH2:6][C@@H:5]([CH3:32])[C:4]([OH:33])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(C(N)=O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(C(N)=O)s1)C(=O)O
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-[(5-carbamoyl-thiophene-2-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester (115 mg, 0.248 mmol) in ethanol (8 mL) is added aqueous 1M NaOH (0.866 mL, 0.866 mmol) and the mixture is stirred at 50° C. for 3.5 hours. The ethanol is removed under reduced pressure and water is added to the residue. The resulting solution is acidified with aqueous 1M HCl and the resulting precipitate is filtered and washed with water. The solid is purified by preparative HPLC using 50% MeCN/water to elute the product. The appropriate fractions are lyophilized to give (2R,4S)-5-biphenyl-4-yl-4-[(5-carbamoyl-thiophene-2-carbonyl)-amino]-2-methyl-pentanoic acid. MS 437.2 (M+1); 1H-NMR (400 MHz, DMSO-d6); δ ppm 1.09 (d, J=7.20 Hz, 3H), 1.57 (m, 1H), 1.88 (m, 1H), 2.46 (m, 1H), 2.84 (m, 2H), 4.18 (m, 1H), 7.28 (d, J=8.21 Hz, 1H), 7.33 (t, 1H), 7.44 (t, 1H), 7.57 (d, J=8.21 Hz, 2H), 7.64 (d, J=7.33, 2H), 7.69 (m, 2H), 8.06 (s, 1H), 8.38 (d, J=8.59 Hz, 1H), 12.07 (s, broad, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(Br)[CH:14]=[C:13]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:24][CH3:25])[CH:11]=2)[NH:6]1)=[O:4].[CH3:27][N:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:12]2[C:7](=[C:8]([N:31]3[CH2:32][CH2:33][CH2:34][N:28]([CH3:27])[CH2:29][CH2:30]3)[CH:9]=[C:10]([O:24][CH3:25])[CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)C1(Br)C=C(OCOCC[Si](C)(C)C)c2cc(OC)ccc2N1
Reactant: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OCOCC[Si](C)(C)C)c2cc(OC)cc(N3CCCN(C)CC3)c2n1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a clear, light brown solution of 2-bromo-6-methoxy-4-(2-trimethylsilanyl -ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (1.01 g, 2.28 mmol), N-methylhomopiperazine (0.32 mL, 2.57 mmol), and 4 Å sieves in 30 mL anhydrous toluene was added Pd2 (dba)2 (43.8 mg, 0.048 mmol) and BINAP (169.8 mg, 0.27 mmol). The resulting wine colored solution was treated with cesium carbonate (1.124 g, 3.45 mmol). The reaction mixture was heated at reflux under nitrogen for 21 hours. The pea green reaction mixture was cooled to room temperature and concentrated. The crude mixture was purified by flash chromatography on silica gel using a gradient of 95:5 to 40:60 methylene chloride: methanol to afford the desired product as a yellow foam (1.004 g, 92%). 1H NMR (300 MHz, DMSO, d6) δ 7.67 (s, 1 H, ArH3), 6.94 (d, 1 H, Jm=2.4 Hz, ArH5), 6.66 (d, 1 H, Jm=2.4 Hz, ArH7), 5.60 (s, 2 H, OCH2O), 3.94 (s, 3 H, CO2CH3), 3.88 (s, 3 H, OCH3), 3.82 (t, 2 H, J=8.0 Hz, OCH2CH2Si), 3.75 (bs, 4 H, ArNCH2CH2CH2NCH3 & ArNCH2CH2N—CH3), 3.45 (bs, 2H, ArNCH2CH2NCH3), 3.31 (bs, 2 H, ArNCH2CH2CH2NCH3), 2.83 (s, 3 H, NCH3), 2.28 (bs, 2 H ArNCH2CH2 CH2NCH3), 0.92 (t, 2 H, J=8.0 Hz, OCH2CH2Si), −0.04 (s, 9 H, Si(CH3)3; Mass Spec.: calc. for [C24H37N3O5Si+H]+ Theor. m/z=476; Obs. 476.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:38][CH2:39][CH:40]1[CH2:44][CH2:43][CH2:42][N:41]1[CH2:45][CH3:46]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:45]([N:41]1[CH2:42][CH2:43][CH2:44][CH:40]1[CH2:39][NH:38][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH:13]=1)[CH3:46]
Reactant: COc1ccc(C(=O)O)cc1OC/C=C(\C)CCC=C(C)C
Reactant: CCN1CCCC1CN
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1ccc(OC)c(OC/C=C(\C)CCC=C(C)C)c1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
3-geranyloxy-4-methoxybenzoic acid(1.52 g) was dissolved in chloroform (50 ml) and triethylamine (1.4 ml), and then diphenylphosphinic chloride(1.0 ml) was added thereto while being cooled with ice. After being stirred for 15 minutes, the mixture, with 2-aminomethyl-1-ethylpyrrolidine(0.7 ml) added thereto, was stirred for 1.5 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1), thereby yielding 1.47 g(71%) of the aimed compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]=[C:11]([O:12][CH2:13][C:14]([OH:16])=O)[C:3]=12.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]=[C:11]([O:12][CH2:13][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[C:3]=12
Reactant: Cc1cc(C)c2c(OCC(=O)O)nsc2n1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c2c(OCC(=O)N3CCOCC3)nsc2n1
Yield: 82 %

Procedure:
Alternatively, the coupling reaction of acid 26 with morpholine in the presence of EDCI, DMAP and DIEA, by a procedure similar to that for compound 21 (YMU1), gave compound 27 in 82% yield.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].C(N(CC)CC)C.[Cl:17][C:18]([Cl:23])([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:1][CH:2]=[CH:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:19](=[O:20])[C:18]([Cl:23])([Cl:22])[Cl:17]
Reactant: COCCNCC=CCl
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(CC=CCl)C(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.7 %

Procedure:
N-(3-chloro)allyl-N-methoxyethylamine (2.25 g, 0.015 mol) and 1.52 g (0.015 mol) triethylamine were stirred in 70 ml dichloromethane. The reaction was kept at approximately 5° C. with an ice-water bath. Trichloroacetyl chloride (2.73 g, 0.015 mol) in 10 ml dichloromethane was added dropwise to the cooled solution. Upon completion of the addition, the mixture was stirred at room temperature for 6 hours. The reaction mixture was then washed twice with saturated brine and dried with sodium sulfate. Rotary evaporation yielded 4.1 g of the above-named product.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C1(OC)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:14]2[C:6]3[C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[S:9][C:5]=3[NH:4][C:3]3[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=3[N:1]=2)[CH2:26][CH2:25]1
Reactant: CCOC(=O)c1c(Nc2ccccc2N)sc2ccccc12
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3ccccc3Nc3sc4ccccc4c32)CC1
Temperature: 25 °C

Procedure:
Ethyl 2-(2-aminoanilino)benzo[b]thiophene-3-carboxylate (3.5 g) and 1-methylpiperazine (20 ml) were dissolved in anisole (50 ml), titanium tetrachloride (3.1 ml) was added dropwise while stirring the mixture at room temperature. After the completion of dropwise addition, the mixture was stirred at 140° C. for 20 hours. The reaction mixture was cooled to 80° C. and poured into ice water. The resultant precipitate was filtrated. The filtrate was extracted with ethyl acetate (900 ml), washed with saturated brine, and dried over MgSO4. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and the obtained oily substance was dissolved in ethyl acetate (50 ml), to which was added a solution (10 ml) of maleic acid (580 mg) in ethyl acetate. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate/methanol to give 12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.2 maleate (1.14 g).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].C[O:6][C:7]1[CH2:11][CH2:10][C:9](=O)[C:8]=1[CH3:13].CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH:8]([C:9]1[CH2:10][CH2:11][C:7](=[O:6])[C:1]=1[CH3:2])=[CH2:13]
Reactant: C=C[Mg]Br
Reactant: COC1=C(C)C(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: C=CC1=C(C)C(=O)CC1
Temperature: 0 °C
Yield: 322.5 %

Procedure:
A one-liter, three-necked flask equipped with a mechanical stirrer, reflux condenser, dropping funnel and nitrogen inlet was flamed out under nitrogen. After 65.6 g (0.05 mole) vinyl magnesium bromide in 500 ml THF was transferred to the reaction flask, 23.3 g (0.18 mole) of 3-methoxy-2-methyl-2-cyclopentenone 7 in 100 ml of dry THF was then added dropwise over a period of several hours. For the reasons supra, methanol with p-toluenesulfonic acid, may be preferred for larger quantity production. The mixture was cooled and then stirred into a four-liter beaker containing 1 kg of cracked ice. After adjustment to pH 3 with concentrated HCl, the reaction mixture was extracted with CHCl3. After washing the combined chloroform extracts with water, the solvent was removed under reduced pressure to give 19.7 g of a yellow liquid. This material was distilled (55°-56° C. at 0.1 mm) to give a 60% yield:nmr (CDCl3) δ7.2-5.2 (m,3, --CH=CH2) and 1.8 (s,3, --CH3).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]([C@H:11]1[CH2:16][C@H:15]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]3[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])[CH2:14][CH2:13][N:12]1C(OC(C)(C)C)=O)=[O:10]>C(Cl)Cl>[Cl:37][C:33]1[C:32]([F:38])=[C:31]([NH:30][C:21]2[C:20]3[C:25](=[CH:26][C:27]([O:28][CH3:29])=[C:18]([O:17][C@@H:15]4[CH2:14][CH2:13][NH:12][C@@H:11]([C:9]([NH2:8])=[O:10])[CH2:16]4)[CH:19]=3)[N:24]=[CH:23][N:22]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H](C(N)=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN[C@@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
TFA (2 ml) was added over a period of 5 minutes to a stirred solution of tert-butyl (2R,4R)-2-(aminocarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1-carboxylate (0.13 g, 0.232 mmol) in DCM (2 ml) at 0° C., was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour after which time, the reaction was complete. The reaction mixture was concentrated to dryness, azeotroped twice with toluene and the residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 5%) to give (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxamide (9) (0.102 g, 100%) as a yellow solid; Mass Spectrum: (M+H)+ 446.1.
Reaction SMILES: [CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C@@:11]([O:18][CH3:19])([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@:9]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([Br:32])[CH:31]=3)[N:22]=2)([CH3:20])[CH2:8][N:7]4[CH3:33])=[CH:3]1.[Br:34]N1C(=O)CCC1=O>O1CCOCC1>[CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C@@:11]([O:18][CH3:19])([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@:9]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([Br:32])[CH:31]=3)[N:22]=2)([CH3:20])[CH2:8][N:7]4[CH3:33])=[C:3]1[Br:34]
Reactant: CO[C@]12C[C@](C)(c3nc(-c4cncc(Br)c4)no3)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Reactant: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Product: CO[C@]12C[C@](C)(c3nc(-c4cncc(Br)c4)no3)CN(C)[C@@H]1Cc1c(Br)n(C)c3cccc2c13
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of 2 g of 1,6-dimethyl-8β-methyl-[3-(5-bromo-pyridin-3-yl)-1,2,4-oxadiazol-5-yl]-10α-methoxy-ergoline in 75 ml of dioxane were added portionwise 0.9 g of N-bromo-succinimide. After stirring at 40° C. for 2 hours, the solvent was removed and the residue was chromatographed on silica gel eluting with ethylacetate.
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:24]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[N:10]([C:35](=[O:37])[CH3:36])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC)cc1)C(C(=O)OC)NCC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC)cc1)C(C(=O)OC)N(C(C)=O)CC2
Reaction time: 8 h

Procedure:
To a mixture of the compound obtained in Example 12 (1.70 g) and pyridine (20 ml) is added acetic anhydride (5 ml), and the mixture is stirred overnight. The solvent is distilled off, and to the resulting residue is added chloroform, and the mixture is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/ethanol=10.1) to give methyl 2-n-butyl-5-acetyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-4,5,6,7-tetrahydroimidazo[4,5 -c]pyridine-4-carboxylate (0.47 g) as an oil.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[N:24]1([CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH:28]=[CH:27][N:26]=[CH:25]1.O>CN(C=O)C>[N:24]1([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([NH:34]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:35][CH:36]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: Nc1ccc(Cn2ccnc2)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(Cn2ccnc2)cc1)c1ccccc1
Yield: 90 %

Procedure:
Prepared from 3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone and 1.5 equivalents of 4-(imidazol-1-yl)methyl-aniline (melting point: 128-130° C.) in DMF (120° C., 1 hour), pouring into water and washing the precipitate with MeOH and ether. Yield: 90% of theory;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]4OCC[O:27]4)[CH:21]=3)=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[CH:26]=[O:27])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)c1cccc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1cccc(C(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)c1
Yield: 95.2 %

Procedure:
To a stirred solution of the product of Example 150 (73 mg, 0.13 mmol) in acetone (4 mL) and water (1 mL) was added pyridinium p-toluenesulfonate (33 mg, 0.13 mmol) and the mixture refluxed for 3.5 h. The acetone was evaporated and the residue diluted with water (10 mL) and extracted into ethyl acetate (2×10 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (10 mL) and brine (20 mL), dried (MgSO4) and evaporated to leave the desired product (64 mg). MS (ES+) 539 ([MNa]+).
Reaction SMILES: C(Cl)Cl.O[CH2:5][C@H:6]1[C@@H:10]([CH2:11][OH:12])[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:7]1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>N1C=CC=CC=1>[CH2:11]1[CH:10]2[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:7][CH:6]2[CH2:5][O:12]1
Reactant: O=C(OCc1ccccc1)N1C[C@@H](CO)[C@@H](CO)C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2COCC2C1

Procedure:
To a mixture of DCM (3 mL) and pyridine (3 mL) was added phenylmethyl (cis)-3,4-bis(hydroxymethyl)-1-pyrrolidinecarboxylate (250 mg, 0.94 mmol) followed by tosyl-chloride (540 mg, 2.8 mmol) and the resulting solution was refluxed for 4 hours. The solvents were evaporated and the residue was azeotroped once with hexane before being purified by RP-HPLC. This yielded phenylmethyl tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-carboxylate (170 mg, 73%). LCMS: (M+H)+: 248.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[NH:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[C:13](=[O:23])[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)[N:16]=[C:7]12)[CH3:2].[Br:25]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:24])[NH:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[C:13](=[O:23])[C:14]([Br:25])=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)[N:16]=[C:7]12)[CH3:2]
Reactant: CCOC(=O)NC1CCCCn2c1nc(-c1ccncn1)cc2=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)NC1CCCCn2c1nc(-c1ccncn1)c(Br)c2=O
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
To a solution of 0.080 g (0.24 mmol) of (4-oxo-2-pyrimidin-4-yl -4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-yl)-carbamic acid ethyl ester in dimethylformamide (4 mL) were added 0.21 g (1.21 mmol) of N-bromosuccinimide and 0.03 g (0.12 mmol) of benzoyl peroxide. The solution was stirred at room temperature for 10 min and at 50° C. for 20 min. The reaction was quenched by adding a saturated solution of ammonium chloride. The product was extracted with dichloromethane, the organic phase was washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 95/5 to afford 58 mg of a solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]([CH:31]=[CH:32][C:33](Cl)=[O:34])[CH:22]=1>C(Cl)Cl>[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]([CH:31]=[CH:32][C:33]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:34])[CH:22]=1
Reactant: O=C(Cl)C=Cc1cnc2ccccc2c1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=Cc1cnc2ccccc2c1)NCCCSc1ccncc1
Yield: 83.8 %

Procedure:
To a solution of 396 mg (1.64 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 0.27 ml (1.97 mmol) of triethylamine in 20 ml of methylene chloride, 500 mg (1.96 mmol) of 3-quinolineacryloyl chloride hydrochlride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain powder. The powder was washed with ether and dried to obtain the desired compound (480 mg, yield: 83.8%, pale yellow powder).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11](OCC)=O)[S:7][C:6]=2[CH:16]=1.[CH2:17]([NH2:20])[CH2:18][NH2:19].[Si](I)(C)(C)C>C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11]3[NH:19][CH2:18][CH2:17][N:20]=3)[S:7][C:6]=2[CH:16]=1
Reactant: NCCN
Reactant: CCOC(=O)c1sc2cc(Br)ccc2c1Cl
Agent: C[Si](C)(C)I
Solvent: CCN(CC)CC
Product: Clc1c(C2=NCCN2)sc2cc(Br)ccc12
Temperature: 80 °C
Reaction time: 120 h

Procedure:
A mixture of 4 g (12.5 mmol) ethyl 6-bromo-3-chlorobenzo[b]thiophen-2-carboxylate and 7.5 g (125 mmol) ethylendiamine were heated at 80° C. overnight. It was concentrated in vacuo, and the crude 2-ethylaminoamide was dissolved in 70 ml dry dichloromethane followed by addition of 10.5 ml triethylamine and 15 g (75 mmol) TMS iodide. After five days stirring at room temperature the reaction was almost complete as detected by TLC. It was extracted with water, dried over sodium sulfate, and concentrated under reduced pressure. The title imidazoline was isolated from the residue by column chromatography on silica gel with dichloromethane/ethanolic ammonia gradient.