Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:22])N(OC)C)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Mg]Br>C1COCC1.CCOCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17](=[O:22])[CH3:23])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5 g of 4-(N-methoxy-N-methyl-carbamoyl)-piperidine-1-carboxylic acid benzyl ester (S. Nahm and S. W. Weinreb, Tetrahedron Letters, 22:3815–3818(1981)) in 50 mL of anhydrous THF cooled to 0° C., was added dropwise 6 mL of 3M methylmagnesium bromide in ether over 10 minutes. After stirring for 1 h at 0° C., the resulting mixture was quenched with 50 mL of 1N HCl and extracted with 3×50 mL of ether. The combined extracts were dried over magnesium sulfate and concentrated to dryness under reduced pressure. Drying under vacuum gave 4-Acetyl-piperidine-1-carboxylic acid benzyl ester as a white solid:
Reaction SMILES: [B-](F)(F)(F)F.[CH:6]1[CH:12]=[CH:11][CH+:10][CH:9]=[CH:8][CH:7]=1.CO.[C:15](=O)(O)[O-:16].[Na+]>O>[CH3:15][O:16][CH:6]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7]1
Reactant: O=C([O-])O
Reactant: c1ccc[cH+]cc1
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1C=CC=CC=C1

Procedure:
1-methoxy-1,3,5-cycloheptatriene can be produced from cycloheptatrienyl tetrafluoroborate (I) as described in Conrow K 1963 Organic Synthesis 43, 101. The reaction of (I) with methanol and sodium bicarbonate in water gives 7-methoxy-1,3,5-cycloheptatriene (II), (reference Conrow K1961, J. Am. Chem. Soc. 83,2342). The 1-methoxy-1,3,5-cycloheptriene can be made by the thermal isomerisation of (II) by heating at 150° for 2.5 hours in nitrogen atmosphere in the presence of antioxidants and absence of water, as described by T. NOZOE and K., Takahashi, Bull Chem. Soc. Japan, 38, 665, 1965. Pratt, J. T. Reaction of Cycloheptatriene, PHD Thesis, University of Washington, Seattle, Wash. 1964.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:8][C:9](=[O:11])[CH3:10])C=CC=CC=1.[F:24][CH2:25][CH2:26][O:27][C:28]1[C:35]([O:36][CH2:37][CH2:38][F:39])=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O>O1CCCC1>[CH3:8][C:9]([CH:10]=[CH:30][C:29]1[C:28]([O:27][CH2:26][CH2:25][F:24])=[C:35]([O:36][CH2:37][CH2:38][F:39])[CH:34]=[CH:33][CH:32]=1)=[O:11]
Reactant: O=Cc1cccc(OCCF)c1OCCF
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)C=Cc1cccc(OCCF)c1OCCF
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
To a stirred, cold (0° C.) solution of 5.2 grams (0.016 mole) 1-triphenylphosphoranylidene-2-propanone in 50 ml of dry tetrahydrofuran was added dropwise a solution of 3.4 grams (0.015 mole) of 2,3-di(2-fluoroethoxy)benzaldehyde in 25 ml of dry tetrahydrofuran. After complete addition the reaction mixture was allowed to warm to room temperature and was then heated at reflux for three hours. The mixture was cooled to room temperature and stirred for approximately 18 hours. The solvent was removed by evaporation under reduced pressure leaving a residue. This residue was partitioned between diethyl ether and water. The organic phase was washed with an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a brown residue. This residue was purified by column chromatography on silica gel, eluting with acetone:n-heptane (20:80), to yield 2.3 grams of 3-(methylcarbonylethenyl)-1,2-di(2-fluoroethoxy)benzene as a solid, mp 71°-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][N:11]1[N:15]=[N:14][CH:13]=[N:12]1.[CH:17](Br)([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:10][N:11]1[N:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(Cn1ncnn1)c1ccc(Cl)cc1Cl
Reactant: CC(C)Br
Product: CC(C)OC(=Cn1ncnn1)c1ccc(Cl)cc1Cl

Procedure:
Analogously to Example 7a,b, after reacting 1-(2,4-dichlorophenyl)-2-tetrazol-2-yl-ethanone with isopropyl bromide there was obtained 2-[2-(2,4-dichloro-phenyl)-2-isopropoxy-vinyl]-2H-tetrazole as a colourless oil. [M]+ =299.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26]>ClCCl>[N+:25]([C:16]1[CH2:17][N:18]([NH:1][CH2:2][C:3]([CH3:5])([NH2:6])[CH3:4])[C:19]2[C:24]([CH:15]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)([O-:27])=[O:26]
Reactant: CC(C)(N)CN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(N)CNN1CC([N+](=O)[O-])=Cc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 1,2-diamino-2-methylpropane (52.20 mL, 503.3 mmol), triethylamine (131.8 mL, 958.8 mmol), and dichloromethane (1.0 L) was chilled in an ice water bath. 4-Chloro-3-nitroquinoline (100.0 g, 479.4 mmol) was added in portions over a period of 5 minutes. The reaction mixture was stirred at 0° C. for 2 hours and then allowed to slowly warm to ambient temperature. After 16 hours the reaction mixture was concentrated under reduced pressure. The residue was triturated with water (500 mL) for 1 hour. The resulting solid was isolated by filtration and dried overnight in a vacuum desiccator to provide 124.6 g of N1-(3-nitroquinolin-1-yl)-2-methylpropane-1,2-diamine as a yellow crystalline solid.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([NH:38][NH2:39])=O)=[CH:34][CH:33]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:36]([C:35]5[CH:40]=[CH:41][C:32]([O:31][CH3:30])=[CH:33][CH:34]=5)=[N:38][N:39]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)cc1
Yield: 36.3 %

Procedure:
The procedure described in example 123 using ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (400 mg, 1.25 mmol), triethylamine (0.5 mL, 3.7 mmol) and 4-methoxy benzhydrazide (415 mg, 2.5 mmol) was used to prepare the title compound (175 mg, 37% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 8.71 (s, 1H), 8.16 (d, 1H), 8.0-8.1 (m, 4H), 7.75 (d, 1H), 7.45 (t, 2H), 7.1 (d, 2H), 3.88 (s, 3H), ES-MS (m/z) 386 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[NH2:39])[CH2:23][CH2:22]1.Cl.O1CCOCC1>CO>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:39][C:28]3[CH:29]=[C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:31]=[CH:32][C:27]=3[N:24]3[CH2:23][CH2:22][O:21][CH2:26][CH2:25]3)=[C:3]([CH3:20])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2cc(Cl)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccc2F)nc2cc(Cl)ccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4,7-dichloro-2-(2-fluorophenyl)-3-methylquinoline (125 mg, 408 μmol), 2,5-dimorpholinobenzenamine (108 mg, 408 μmol) and 4N hydrochloric acid solution in dioxane (0.10 mL, 408 μmol) in MeOH (3.00 mL) to afford product as a colorless solid after purification by chromatography on silica gel, eluting with MeOH gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 8.02 (1H, d, J=2.3 Hz), 7.72 (1H, d, J=9.0 Hz), 7.46 (1H, td, J=7.4, 2.0 Hz), 7.26-7.40 (2H, m), 7.17-7.25 (1H, m), 7.13 (1H, s), 7.02-7.10 (1H, m), 6.98 (1H, d, J=8.6 Hz), 6.31 (1H, dd, J=8.6, 2.7 Hz), 5.91 (1H, br. s.), 3.77 (4H, t, J=4.7 Hz), 3.59-3.68 (4H, m), 2.91 (4H, br. s.), 2.74-2.87 (4H, m), 2.06 (3H, d, J=2.0 Hz). Mass Spectrum (ESI) m/e=533.2 (M+1).
Reaction SMILES: [CH2:1]([C:5]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=1)(C(OCC)=O)[C:6]([O:8]CC)=[O:7])[CH:2]([CH3:4])[CH3:3].O.OS(O)(=O)=O>C(O)(=O)C>[CH3:3][CH:2]([CH3:4])[CH2:1][CH:5]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([C:25]([F:26])([F:27])[F:28])[CH:17]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(CC(C)C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CC(C(=O)O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 75.7 %

Procedure:
To a solution of diethyl 2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate (74.4 g, 184 mmol) in acetic acid (500 mL) were added water (157 mL) and concentrated H2SO4 (55 mL) carefully. The reaction mixture was refluxed for three days and then concentrated under reduced pressure. The residue was diluted with water (400 mL) and extracted with ethyl acetate (6×100 mL). The combined organic extracts were washed with water (400 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a brown oil. The residue was purified by silica-gel flash chromatography eluting with heptane/EtOAc (5:1 and then 2:1) to give 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid (42.5 g, 76%) as a yellowish oil: 1H NMR (300 MHz, CDCl3): δ 11.51 (s, 1H, br), 7.87 (d, 1H, J=8.4 Hz), 7.78 (s, 1H), 7.71 (d, 1H, J=8.4 Hz), 3.84 (t, 1H, J=7.8 Hz), 2.06 (m, 1H), 1.72 (m, 1H), 1.49 (m, 1H), 0.95 (d, 3H, J=6.6. Hz), 0.94 (d, 3H, J=6.3 Hz); 13C NMR (75 MHz, CDCl3): δ 178.76, 147.09, 143.94, 132.66, 127.70 (q, J=5 Hz), 125.40, 123.95 (q, J=34 Hz), 121.74 (q, J=271 Hz), 42.16, 25.96, 22.44, 22.09.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][NH:16]O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.N1C=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][OH:40]>CO>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][NH:16][CH2:37][CH2:36][CH2:35][CH2:34][CH2:39][OH:40])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccccn1
Reactant: ONCc1c2ccccc2cc2ccccc12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CO
Product: OCCCCCNCc1c2ccccc2cc2ccccc12
Reaction time: 8 h

Procedure:
The General Procedure for the N-Boc protection of N-(Anthracen-9-ylmethyl)amino alcohols 4 to give 5. The solution of N-(anthracen-9-ylmethyl)-amino alcohol (5 mmol) in 20 mL of pyridine-methanol (1:5 v/v) was stirred at 0° C. for 10 min. A solution of di-tert-butyl dicarbonate (7.5 mmol) in methanol (5 mL) was added dropwise over ten minutes. The temperature was allowed to rise to room temperature and the reaction was stirred overnight. The mixture was evaporated to dryness under reduced pressure. The residue was dissolved in methylene chloride, and washed with deionized water several times. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([C@H:31]1[O:33][CH2:32]1)[Cl:30].[O-]S([O-])(=O)=O.[Mg+2]>CO>[CH2:21]([N:20]([CH2:32][C@H:31]([OH:33])[CH2:29][Cl:30])[CH2:19][CH2:18][CH2:17][CH2:16][C@H:7]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNCc1ccccc1)C(=O)OC(C)(C)C
Reactant: ClC[C@@H]1CO1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN(Cc1ccccc1)C[C@H](O)CCl)C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 66.9 %

Procedure:
A mixture of Nε -benzyl-Nα -BOC-L-lysine t-butyl ester (4) (16.0 g, 40.76 mmol), CH3OH (40 ml), (S)-(+)-epichlorohydrin (4.17 g, 45.0 mmol) and anhydrous MgSO4 (5.33 g. 44.28 mmol) was stirred under N2 for three days. The solids were filtered off and washed with CH3OH. The filtrate was concentrated at room temperature to give a yellow oil. The resulting oil was purified by flash chromatography on silica gel (66% hexane/ethyl acetate) to give 13.23 g of (5) (77%) as a colorless oil. 1H NMR (C6D6) δ7.18 (m, 5H), 5.00 (br d, 1H), 4.40 (m, 1H), 3.62 (m, 1H), 3.40-3.10 (m, 4H), 2.20-2.00 (m, 4H), 1.63 (m, 1H), 1.40 (s, 9H), 1.31 (s, 9H), 1.20 (m, 2H). 13C NMR (C6D6) δ171.7, 155.2, 138.8, 128.8, 127.9, 127.0, 80.8, 78.8, 67.7, 58.8, 57.2, 53.9, 53.7, 47.3, 32.5, 28.0, 27.5, 26.3, 22.8. HRMS m/z calcd. for C25H42ClN2O5 485.2782, found 485.2775. [α]25D +5.3° (c=1.00, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9]2[CH:10]=[N:11][N:12]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1)=[O:7].[OH-:30].[K+].OO.O>C(O)C.O>[C:28]([C:26]1[CH:25]=[CH:24][C:3]([CH2:4][NH:5][C:6]([C:8]2[C:9]3[CH:10]=[N:11][N:12]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[C:13]=3[CH:14]=[CH:15][CH:16]=2)=[O:7])=[C:2]([Cl:1])[CH:27]=1)(=[O:30])[NH2:29]
Reactant: [OH-]
Reactant: N#Cc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)c(Cl)c1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)c(Cl)c1

Procedure:
To a suspension of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid 2-chloro-4-cyano-benzylamide in a 1:1 mixture of EtOH—H2O (2.0 mL) was added KOH (0.018 g, 0.32 mmol) and a 30% solution of H2O2 in H2O (0.13 mL, 1.1 mmol). The suspension was sealed and heated briefly to dissolve the mixture. The resultant solution was stirred at room temperature for 16 hours, during which time a solid precipitated. The mixture was diluted with H2O (10 mL) and the solid was collected by filtration and dried to afford the title compound as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].CCN(C(C)C)C(C)C>Cl[Pd]Cl.CN(C)C=O>[F:10][C:4]1[CH:3]=[C:2](/[CH:13]=[CH:12]\[C:11]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[C:6]([F:8])[C:5]=1[OH:9]
Reactant: C=CC(=O)OCC
Reactant: Oc1c(F)cc(Br)cc1F
Agent: Cl[Pd]Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C\c1cc(F)c(O)c(F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-2,6-difluorophenol (6.3 g, 30.15 mmol, 1.00 equiv), ethyl prop-2-enoate (17.2 g, 171.80 mmol, 5.70 equiv), P(toly)3 (18.24 g), DIEA (11.6 g, 89.76 mmol, 2.98 equiv), PdCl2 (0.531 g), N,N-dimethylformamide (100 mL). The resulting solution was stirred overnight at 80° C. The reaction was then quenched by the addition of 30 mL water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30/70). The collected fractions were combined and concentrated under vacuum. This resulted in 6 g (79%) of ethyl (2Z)-3-(3,5-difluoro-4-hydroxyphenyl)prop-2-enoate as yellow oil. Mass spectrum (ESI, m/z): Calcd. for C11H10F2O3, 229.1 (M+H). found 229.1
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:30])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24]OS(C)(=O)=O)[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[SH:37]>>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][S:37][C:33]3[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=3)[N:22]=2)=[O:30])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CCOS(C)(=O)=O)cs2)c(C(=O)C2CCCC2)c1
Reactant: Cn1ccnc1S
Product: Cc1ccc(NC(=O)Nc2nc(CCSc3nccn3C)cs2)c(C(=O)C2CCCC2)c1
Yield: 43.6 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-{4-[2-(1-methyl-1H-imidazol-2-ylsulfanyl)-ethyl]-thiazol-2-yl}-urea (45 mg, 43%) was prepared from methanesulfonic acid 2-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-ethyl ester (0.10 g, 0.22 mmol) and 1-methyl-1H-immidazole-2-thiol (0.04 g, 0.33 mmol) following the general procedure Z.
Reaction SMILES: [CH:1]([C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:18]SC1C(C2C=NC=CC=2)=NNC=1>C(OCC)C>[CH:1]([C:7]1[C:8]([C:12]2[CH2:13][N:14]([CH3:18])[CH2:15][CH2:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC=Cc1c[nH]nc1-c1cccnc1
Reactant: CSc1c[nH]nc1-c1cccnc1
Solvent: CCOCC
Product: CCCCC=Cc1c[nH]nc1C1=CCCN(C)C1

Procedure:
Compound 46A (0.34 g, 0.97 mmol), 0.7 g of KOH and 1 ml of NH2NH2.H2O were combined in diethylene glycol (10 ml) and warmed to reflux for 1 hour under N2. The mixture was cooled, concentrated and redissolved in MeOH. Filtration over 25 g of SCX-2 (MeOH followed by 1 N NH3/MeOH) and subsequent purification by flash chromatography (ethyl acetate) afforded 3-(4-hex-1-enyl-1H-pyrazol-3-yl)-pyridine (the deprotected analog of 46A). Yield 0.18 g (86%). (TLC diethyl ether Rf 0.18). 3-(4-Hex-1-enyl-1H-pyrazol-3-yl)-pyridine was converted to the title compound 47A, using the methodology described for the conversion of 21A to 22A (see Scheme 3).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:17][C:16]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:15]=3[C:14](=[O:23])[NH:13][C:12]=2[CH:24]=1)(=O)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:15]2[C:14](=[O:23])[NH:13][C:12]3[CH:24]=[C:8]([CH2:7][CH2:6][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:9]=[CH:10][C:11]=3[NH:17][C:16]=2[CH:18]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(CCN3CCOCC3)ccc2Nc2cc(Cl)ccc21
Temperature: 50 °C

Procedure:
A mixture of Example 641A (360 mg, 0.98 mmol) in DMF (5 mL) was treated with morpholine (200 μL) and heated at 50° C. for 24 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel to provide the title compound. MS (ESI) m/e 358 (M+H)+; 1H NMR (300 MHz, DMSO-d.6 □ 9.84 (s, 1H), 7.97 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.91 (dd, J=8.5, 2.0 Hz, 1H), 6.81-6.89 (m, 3H), 3.55-3.58 (m, 4H), 2.57-2.62 (m, 2H), 2.37-2.45 (m, 6H).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:33][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]([CH3:15])=[C:13]2[CH:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])(=[O:24])=[O:23])[CH2:18][CH2:17]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3ccccc3OC)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)N1CCC(c2c(C)c(CC(=O)O)cc3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of {6-fluoro-4-[1-(2-methoxy-benzenesulfonyl)-piperidin-4-yl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (64 mg, 0.132 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (63.3 mg, 1.5 mmol) in water (2 mL). The reaction mixture was stirred at room temperature overnight under nitrogen. After this time, the reaction mixture was concentrated. Water (˜20 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (2.7 mL). The resulting white precipitate was collected by vacuum filtration, washed with hexanes, and then further dried under vacuum to provide {6-fluoro-4-[1-(2-methoxy-benzenesulfonyl)-piperidin-4-yl]-3-methyl-naphthalen-2-yl}-acetic acid (51.5 mg, 83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.45 (br. s, 1H), 8.04 (br. s, 1H), 7.85-7.92 (m, 1H), 7.78-7.84 (m, 1H), 7.67 (s, 2H), 7.29-7.37 (m, 2H), 7.13 (t, J=8.00 Hz, 1H), 3.94 (s, 3H), 3.82-3.92 (m, 2H), 3.70-3.80 (m, 2H), 2.82-3.02 (m, 2H), 2.35 (s, 3H), 2.13-2.32 (m, 1H), 1.60-1.71 (m, 2H). MS cald. for C25H27FNO5S [(M+H)+]: 472, obsd. 472.2.
Reaction SMILES: C[O:2][C:3]1C(OC)=CC2N(CC)C(=O)C(CC3C=CC=CC=3N)N=C(C3C=CC=CC=3)C=2[CH:30]=1.[CH3:33][O:34][C:35]1[C:36]([O:64][CH3:65])=[CH:37][C:38]2[N:44](CC)[C:43](=[O:47])[CH:42]([CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[CH2:55][NH2:56])[N:41]=[C:40]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:39]=2[CH:63]=1>>[CH3:33][O:34][C:35]1[C:36]([O:64][CH3:65])=[CH:37][C:38]2[NH:44][C:43](=[O:47])[CH:42]([C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=3[CH2:50][CH2:55][NH:56][C:3](=[O:2])[CH3:30])[N:41]=[C:40]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C:39]=2[CH:63]=1
Reactant: CCN1C(=O)C(Cc2ccccc2CN)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Reactant: CCN1C(=O)C(Cc2ccccc2N)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Product: COc1cc2c(cc1OC)C(c1ccccc1)=NC(c1ccccc1CCNC(C)=O)C(=O)N2
Yield: 55 %

Procedure:
By replacing 7,8-dimethoxy-1-ethyl-3-(2-aminobenzyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIca) in example IIcf by 7,8-dimethoxy-1-ethyl-3-(2-aminomethylbenzyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIcg) and proceeding in the same manner, the abovenamed product is obtained. Yield: 55%. M: 122–124° C. 1H-NMR (CDCl3, 200 MHz): d 1.07–1.14 (m, 3H, CH3), 1.49 (s, 1H, COCH3), 3.41–3.80 (m, 6H, CHCH2+1HNCH2+OCH3), 3.89–3.98 (m, 4H, CHCH2+OCH3), 4.34–4.45 (m, 1HNCH2), 6.60 (s, 1H Ar), 4.55–4.57 (m, 2H, CH2NHAc), 6.52 (s, 6.85 (s, 1H Ar), 7.18–8.45 (m, 9H Ar), 8.45 (m, 1H, NHAc).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[NH:10][CH:9]=2)=[CH:4][CH2:3]1.CN1CCCC1=O.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1>ClCCl>[Si:25]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CN1C=CC(c2c[nH]c3ccc(O)cc23)=CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CN1CCC(c2c[nH]c3ccc(O[Si](C)(C)C(C)(C)C)cc23)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 3-(1-methyl-pyridin-4-yl)-5-hydroxy-1H-indole (8.0 g, 34.7 mmol) and 1-methyl-2-pyrrolidinone (10 mL) in dichloromethane (90 mL) stirring at 0° C., was added tert-butyldimethylsilyl chloride in small portions (5.50 g, 36.5 mmol), followed by imidazole also in small portions (2.48 g, 36.5 mmol). The reaction mixture was stirred for 1 hour at 0° C., then overnight at room temperature. The mixture was concentrated in vacuo to a solid residue, which was directly purified on silica gel. Elution with a 9:1 mixture of dichloromethane and methanol provided 7.60 g (63%) of the title compound as a white solid: mp=191-195° C.; 1H NMR (400 MHz, dmso-d6): 10.46 (s, 1H), 7.02 (d, 1H, J=8.4 Hz), 6.87 (d, 1H, J=2.4 Hz), 6.74 (d, 1H, J=2.4 Hz), 6.45 (dd, 1H, J=8.6, 2.6 Hz), 2.69 (br d, 2H, J=11.2 Hz), 2.46 (tt, 1H, J=11.8, 3.6 Hz), 2.04 (s, 3H), 1.92-1.80 (m, 2H), 1.75-1.67 (m, 2H), 1.50 (qd, 2H, J=12.4, 3.6 Hz), 0.81 (s, 9H), 0.00 (s, 6H); MS (APCI): m/e 345 0.2 (M+1).