Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[C:6](C2C=C3C(=CC=2)NC(C)(C)C=C3C)[CH:7]=1.[I:24]C1C=C(C=C([N+]([O-])=O)C=1)N>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[C:6]([I:24])[CH:7]=1
Reactant: Nc1cc(I)cc([N+](=O)[O-])c1
Reactant: CC1=CC(C)(C)Nc2ccc(-c3cc(F)cc([N+](=O)[O-])c3)cc21
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)cc(I)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
6-(5-Fluoro-3-nitrophenyl)-1,2-dihydro-2,2,4-trimethylquinoline (Compound 280, structure 4 of Scheme II, where R1 =5-fluoro-3-nitrophenyl) 1-Fluoro-3-nitroidobenzene To a 25 mL round-bottom flask equivuipped with a magnetic stir bar 3-iodo-5-nitroaniline (543.3 mg 2.06 mmol) and methylene chloride (10 mL) were added under nitrogen. Nitrogen was bubbled through the colorless solution for 15 min. The solution was cooled to 0° C. in an ice bath. At that point approximately 500 mg nitrosonium tetrafluoroborate was added in one portion making a cloudy precipitate. The reaction was allowed to continue stirring for 2 hours. The mixture was kept under nitrogen as 10 mL dry, deoxygenated ortho-dichlorobenzene was added. A distillation apparatus was fitted to the reaction flask. The flask was place din an oil bath and was heated until the material had completely distilled over. The crude product was isolated by washing the residue through a short column (74 mL silica, hexane). Purification by silica gel chromatography (74 mL silica, hexane) afforded 279.4 mg (50%) of 5-fluoro-3-nitroiodobenzene. Data for 5-fluoro-3-nitroiodobenzene: 1H NMR (400 MHz, acetone-d6) 8.36 (s, 1 H), 8.00 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].I[CH3:14]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:14]
Reactant: CI
Reactant: Brc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-1H-indole (6.7 g) in tetrahydrofuran (75 ml) was treated with sodium hydride (1.24 g) and stirred for 0.5 h at room temperature. The resulting suspension was treated with a solution of iodomethane (2.34 ml) in tetrahydrofuran (35 ml) at 0° C. and allowed to warm to room temperature over 1 h, whilst stirring. The reaction mixture was poured onto water and partitioned between dichloromethane and water. The organic phase was dried over (MgSO4) and concentrated in vacuo to afford the title compound (7.2 g). TLC Silica (cyclohexane-ethyl acetate [1:1]), Rf=0.55.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3](=[O:14])[C:4]([N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)=[CH:5]N(C)C.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O.Cl>CCOCC>[CH:17]1([CH:5]=[C:4]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)[C:3](=[O:14])[C:2]([CH3:1])([CH3:15])[CH3:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Br[Mg]C1CCCCC1
Reactant: CN(C)C=C(C(=O)C(C)(C)C)n1cncn1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)C(=O)C(=CC1CCCCC1)n1cncn1
Reaction time: 1 h
Yield: 82.6 %

Procedure:
11.1 g (0.05 mol) of 4,4-dimethyl-1-dimethylamino-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one were dissolved in 250 ml of ether. An ethereal solution of 13.1 g (0.07 mol) of cyclohexyl-magnesium bromide was added dropwise to this solution in the course of 30 minutes. The reaction mixture was subsequently stirred for one hour, 250 ml of water were added and the mixture was adjusted to a pH value of 6-7 with hydrochloric acid. The organic phase was separated off, dried and filtered and the filrate was concentrated. 10.8 g (83% of theory) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one of refractive index nD20 1.5003 were obtained.
Reaction SMILES: I[CH2:2][C:3]([NH:5][CH2:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[C:11](=[C:12]3[C:17](=[CH:18][C:19]=2[NH2:23])[CH:16]=[CH:15][CH:14]=[N:13]3)[N:10]=1)=[O:8])=[O:4].[NH3:24]>CN(C)C=O>[NH2:24][CH2:2][C:3]([NH:5][CH2:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[C:11](=[C:12]3[C:17](=[CH:18][C:19]=2[NH2:23])[CH:16]=[CH:15][CH:14]=[N:13]3)[N:10]=1)=[O:8])=[O:4]
Reactant: Nc1cc2cccnc2c2nc(C(=O)CNC(=O)CI)ccc12
Reactant: N
Solvent: CN(C)C=O
Product: NCC(=O)NCC(=O)c1ccc2c(N)cc3cccnc3c2n1
Reaction time: 1 h

Procedure:
(Iodoacetyl-glycyl)-5-amino-1,10-phenanthroline (6) (Preparation 5; 32.3 mg; 77.0 μmol) was dissolved in 2 ml dimethylformamide. Into this solution, was added 10 ml concentrated ammonia. The reaction mixture was stirred for 1 hr. in the dark, and then was evaporated under vacuum. The crude product was purified by preparative thin layer chromatography (silica; 2000 μm; ammonia:95% ethanol, 1:20, v/v). Yield: 10.5 mg, 44%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[S:21][C:20]([N:22]3[CH2:28][CH2:27][CH2:26][NH:25][C:24](=[O:29])[CH2:23]3)=[N:19][CH:18]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.ClC1C=CC=C(C(OO)=[O:38])C=1>ClCCl.[O-]S([O-])(=S)=O.[Na+].[Na+]>[CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[S:21][C:20]([N:22]3[CH2:28][CH2:27][CH2:26][NH:25][C:24](=[O:29])[CH2:23]3)=[N:19][CH:18]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([S:15]([CH3:16])=[O:38])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: CSc1ccnc(Nc2cc(C)cc(-c3cnc(N4CCCNC(=O)C4)s3)c2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(S(C)=O)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Reaction time: 3 h
Yield: 6.4 %

Procedure:
To 4-[5-(3-methyl-5-{[4-(methylsulfanyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (50 mg, 0.117 mmol) stirring in dichloromethane (586 μL) at room temperature was added 3-chloroperbenzoic acid (27.6 mg, 0.123 mmol). Stirred for 3 hr. at room temperature, diluted with 10% Na2S2O3 (aq.), and washed with sat. NaHCO3 (aq.) and brine. The organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purified by reverse phase preparative HPLC (0:100 to 95:5 acetonitrile:water: 0.1% v/v trifluoroacetic acid modifier) to afford 4-[5-(3-methyl-5-{[4-(methylsulfinyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (3.3 mg, 7.5 μmol, 6.36% yield) as a yellow solid. MS APCI: [M+H]+ m/z 443.1. 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J=4.9 Hz, 1H), 7.68 (s, 1H), 7.48 (s, 1H), 7.44 (d, J=4.9 Hz, 1H), 7.34-7.29 (m, 1H), 7.19 (s, 1H), 6.96 (s, 1H), 5.93-5.85 (m, 1H), 4.28 (s, 2H), 3.46 (s, 2H), 2.93 (s, 2H), 2.37 (s, 3H), 2.16-2.01 (m, 2H), 1.25 (s, 3H). rhSYK activity=+++.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Br:18][C:19]1[CH:32]=[CH:31][C:22]2[NH:23][C:24]([C@@H:26]([NH2:30])[CH2:27][O:28][CH3:29])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Br:18][C:19]1[CH:32]=[CH:31][C:22]2[NH:23][C:24]([C@@H:26]([NH:30][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][O:28][CH3:29])=[N:25][C:21]=2[CH:20]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Reactant: COC[C@H](N)c1nc2cc(Br)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c(C)c1)c1nc2cc(Br)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:20]([CH2:34][C:35]3[C:36]([C:41]#[N:42])=[N:37][CH:38]=[CH:39][CH:40]=3)[CH2:21][CH2:22][N:23]3[CH:28]=[CH:27][C:26]4[O:29][C:30]([CH3:32])=[CH:31][C:25]=4[C:24]3=[O:33])[CH:17]=[CH:18][C:4]1=2)[CH3:2].C[C:44](C)=[O:45]>[Ni].C(O)=O>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:20]([CH2:34][C:35]3[C:36]([CH2:41][NH:42][CH:44]=[O:45])=[N:37][CH:38]=[CH:39][CH:40]=3)[CH2:21][CH2:22][N:23]3[CH:28]=[CH:27][C:26]4[O:29][C:30]([CH3:32])=[CH:31][C:25]=4[C:24]3=[O:33])[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CC(C)=O
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3C#N)ccc21
Agent: [Ni]
Solvent: O=CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3CNC=O)ccc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
3-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridine-2-carbonitrile (0.40 g) and Raney nickel (1.2 g) were suspended in formic acid (8 ml), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=75:25→80:20). The purified product was condensed under reduced pressure. Acetone and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (33 mg) as a pale brown white amorphous.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH2:31])[CH:20]=1>C(N(CC)CC)C>[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([NH:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][CH2:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1
Reactant: NCCOCCCc1cccnc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCCCc2cccnc2)c1C
Temperature: 45 °C

Procedure:
Anhydrous N,N-dimethylformamide (200 ml), anhydrous triethylamine (12.1 ml), and 2,4-dichloro-5,6-dimethyl-3-nitropyridine (16.05 g) were combined and 2-(3-pyridin-3-ylpropoxy)ethylamine (14.4 g) was then added with stirring. The pale yellow reaction mixture was heated to 45° C. under a nitrogen atmosphere for 1 hour. HPLC analysis indicated that the reaction was sufficiently complete to proceed. The reaction mixture was allowed to cool and the solvent was removed under reduced pressure. The resulting oil was dissolved in ethyl acetate and washed twice: once with a saturated aqueous solution of ammonium chloride and once with water. The organic layer was then extracted 3 times with brine, dried with magnesium sulfate, and concentrated under reduced pressure. The product was passed through a silica gel column using 90/10 ethyl acetate/hexane as the eluant. The resulting oil was dried under vacuum at 60° C. for 2 hours. NMR analysis indicated sufficient purity for use of the product in the next step.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][CH2:10][C:11]=2[CH:12]=1)[NH2:2].[C:17](/[N:19]=[C:20](\OC1C=CC=CC=1)/[NH:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[C:24]([F:39])[CH:23]=1)#[N:18]>C(O)(C)C>[N:5]1[C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][CH2:10][C:11]=2[CH:12]=[C:3]([N:1]2[C:17]([NH2:18])=[N:19][C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][CH:31]([N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:30][CH2:29]4)=[C:24]([F:39])[CH:23]=3)=[N:2]2)[N:4]=1
Reactant: N#C/N=C(/Nc1ccc(N2CCC(N3CCCC3)CC2)c(F)c1)Oc1ccccc1
Reactant: NNc1cc2c(nn1)-c1ccccc1CC2
Solvent: CC(C)O
Product: Nc1nc(Nc2ccc(N3CCC(N4CCCC4)CC3)c(F)c2)nn1-c1cc2c(nn1)-c1ccccc1CC2

Procedure:
3-Hydrazinyl-5,6-dihydrobenzo[h]cinnoline (51 mg, 0.24 mMol) and (Z)-phenyl N′-cyano-N-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)carbamimidate (98 mg, 0.24 mMol) were suspended in isopropanol (3 mL) and subjected to microwave irradiation (150° C., 20 min). The crude product was purified by radial chromatography on silica gel, eluting with 95% dichloromethane and 5% 2M ammonia in methanol to give 1-(5,6-dihydrobenzo[h]cinnolin-3-yl)-N3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #170; 1H NMR (CDCl3/MeOD4, 300 MHz) 10.84 (s, 1H), 8.43 (d, 1H), 7.75 (s, 1H), 7.61 (d, 1H), 7.41 (m, 2H), 7.26 (m, 2H), 6.93 (t, 1H), 3.42 (m, 2H), 3.00 (m, 3H), 2.60-2.75 (m, 6H), 2.15 (m, 1H), 1.98 (m, 2H), 1.74-1.95 (m, 7H) ppm; MS (ES) 526.43 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].IC.[C:26]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:26][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1C
Reaction time: 16 h

Procedure:
A solution of ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate (1.0 g, 3.23 mmol) and iodomethane (2.5 mL, 40.2 mmol) in DMF (25 mL) was treated with Cs2CO3 (3.26 g, 10 mmol) and stirred for 16 h. The reaction was quenched by addition of water and the solid was collected and dried to yield ethyl 1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylate (I13064-48) as a yellowish solid (1.1 g, 100%): 1H NMR (DMSO-d6) δ 1.03 (t, J=7.0 Hz, 3 H), 4.09 (s, 3 H), 4.18 (q, J=7.0 Hz, 2 H), 7.40-7.55 (m, 5 H), 7.90 (d, J=9.2 Hz, 1 H), 8.23 (dd, J=9.2, 2.3 Hz, 1H), 8.32 (d, J=2.3 Hz, 1 H); MS (EI) m/z 325.2 (MH+).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH:6]([C@H:8]([NH:19][C:20]([O:22][CH3:23])=[O:21])[C:9]([O:11]CC2C=CC=CC=2)=[O:10])[CH2:5][C@@H:4]([CH3:24])[O:3]1>CO.[Pd]>[CH3:1][C@@H:2]1[CH2:7][CH:6]([C@H:8]([NH:19][C:20]([O:22][CH3:23])=[O:21])[C:9]([OH:11])=[O:10])[CH2:5][C@@H:4]([CH3:24])[O:3]1
Reactant: COC(=O)N[C@H](C(=O)OCc1ccccc1)C1C[C@@H](C)O[C@H](C)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)N[C@H](C(=O)O)C1C[C@@H](C)O[C@H](C)C1
Reaction time: 8 h
Yield: 100.1 %

Procedure:
(S)-Benzyl 2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonylamino)acetate (Cap-2, step e) (56 mg, 0.167 mmol) was dissolved in MeOH (4 mL) and then treated with 10% Pd/C (12 mg, 0.012 mmol). The reaction mixture was vacuum flushed with nitrogen (4×) and then with hydrogen (4×) and stirred under a balloon of hydrogen overnight. The reaction was filtered through Celite® and concentrated to yield (S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonylamino)acetic acid (Cap-2) (41 mg) as a colorless oil. 1H NMR (400 MHz, D4-MeOH) δ ppm 4.22 (quin, J=6.4 Hz, 1H), 4.04-4.11 (m, 1H), 3.78-3.87 (m, 1H), 3.66 (s, 3H), 2.26-2.39 (m, 1H), 1.63 (d, J=13.1 Hz, 1H), 1.51-1.60 (m, 1H), 1.42-1.49 (m, 1H), 1.27 (d, J=7.0 Hz, 3H), 1.11 (d, J=6.3 Hz, 3H), 0.97-1.08 (m, 1H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Mg].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1>C1COCC1>[F:29][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([C@H:10]3[CH2:11][CH2:12][Si@H:7]([CH2:1][CH2:2][CH3:3])[CH2:8][CH2:9]3)[CH2:14][CH2:15]2)[CH:26]=[C:25]([F:27])[C:24]=1[F:28]
Reactant: Fc1cc(CC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc(F)c1F
Reactant: CCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCc3cc(F)c(F)c(F)c3)CC2)CC1

Procedure:
2.5 g (20 mmol) of n-propyl bromide was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.8 g (20 mmol) of 1-chloro-4-(trans-4-(2-(3,4,5-trifluorophenyl) ethyl) cyclohexyl)-1-silacyclohexane. The silacyclohexane rings of the reacted mixture thus obtained were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 6.1 g (yield 80%) of trans-4-(trans-4-(2-(3,4,5-trifluorophenyl) ethyl) cyclohexyl)-1-n-propyl-1-silacyclohexane.
Reaction SMILES: C[O-].[Na+].[CH2:4]([SH:6])[CH3:5].[CH3:7][C:8]1([CH3:31])[CH:17](OS(C)(=O)=O)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:24]([O:26]CC)=[O:25])[C:15]=2[CH3:23])[S:10](=[O:30])(=[O:29])[CH2:9]1>CO.C(OCC)(=O)C>[CH3:7][C:8]1([CH3:31])[CH:17]([S:6][CH2:4][CH3:5])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:24]([OH:26])=[O:25])[C:15]=2[CH3:23])[S:10](=[O:29])(=[O:30])[CH2:9]1
Reactant: CCS
Reactant: CCOC(=O)c1ccc2c(c1C)C(OS(C)(=O)=O)C(C)(C)CS2(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCSC1c2c(ccc(C(=O)O)c2C)S(=O)(=O)CC1(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
A methanolic solution of 0.8 g (4 mmol, 3 eq.) containing about 28 wt % sodium methoxide was diluted with 5 ml of anhydrous methanol, and 0.5 ml (6.8 mmol, 1.5 eq.) of ethanethiol was added. The mixture was stirred at room temperature for 5 minutes, and then 0.5 g (1.3 mmol) of 3,3,5-trimethyl-4-methanesulfonyloxy-6-ethoxycarbonylthiochroman-1,1-dioxide was added. The mixture was refluxed for 8 hours, and allowed to stand at room temperature for 5 days. The reaction mixture was diluted with 100 ml of ethyl acetate and washed with 50 ml of water twice, and an aqueous layer was separated and cooled in an ice bath. The aqueous layer was acidified with 5 wt % hydrochloric acid and extracted with 100 ml of ethyl acetate, and an organic layer was dried over sodium sulfate. The solvent was distilled off, and the residue was dried under reduced pressure to give 0.32 g (yield 75%) of a yellowish solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[C@H:10]([CH3:18])[NH:11][C:12](=[O:17])[C@H:13]([CH3:16])[NH:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([NH:27][C@H:28]([C:32](O)=[O:33])[CH:29]([CH3:31])[CH3:30])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>ClCCl>[CH2:1]([O:8][C:9](=[O:19])[C@H:10]([CH3:18])[NH:11][C:12](=[O:17])[C@H:13]([CH3:16])[N:14]([C:32](=[O:33])[C@H:28]([CH:29]([CH3:30])[CH3:31])[NH:27][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1

Procedure:
A mixture of 10.75 g (0.0407 mole) of N-methyl-L-alanyl-L-alanine benzyl ester and 9.73 g (0.0448 mole) of Boc-L-valine in 200 ml of dry dichloromethane was stirred and cooled at -10° C. as 9.97 g (0.0986 mole) of triethylamine was added. After stirring for 15 minutes, 12.55 g (0.0493 mole) of BOP-Cl was added and the reaction was stirred at -5° C. for 22 hours. The reaction was diluted with 100 ml of dichloromethane, washed with 100 ml of 10% potassium bisulfate, washed with 2×75 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, concentrated, and chromatographed on silica gel using 1:1 ether/hexane as the eluent. The product weighed 17.1 g (91% of theory). Its 200 MHz NMR spectrum in chloroform-d was consistent with the proposed structure.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:10]([CH3:25])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=C=O)=[CH:36][CH:35]=1>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([NH:40][C:37]4[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=4)=[O:5])[CH2:9][CH:10]3[CH3:25])=[CH:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccnc2cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CN(C(=O)Nc2ccc(F)cc2)CCN1c1ccnc2cc(Cl)ccc12

Procedure:
4-[4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl]-7-chloroquinoline (0.30 g, 0.8 mmol) is deprotected with TFA in CH2Cl2 and transformed after being washed with base into the product according to method C using 4-fluorophenyl isocyanate (61 μL, 0.54 mmol) to give the title product a colorless solid.
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[CH2:21]([OH:24])[C:22]#[CH:23].[Cl-].[NH4+]>N1CCCC1.[Cu]I>[OH:24][CH2:21][C:22]#[C:23][C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: C#CCO
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCNC1
Product: OCC#Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Temperature: 75 °C
Reaction time: 5 h
Yield: 183.4 %

Procedure:
To a stirred solution of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (9.7 g, 25 mmol) and tetrakis (triphenylphosphine)palladium(0) (2.9 g, 5 mmol) in pyrrolidine (75 ml) was added a solution of 2-propyn-1-ol (5.6 g, 0.1 mol) in pyrrolidine (75 ml), then copper (I) iodide (475 mg, 2.5 mmol). The resulting solution was heated to 75° C. with stirring under nitrogen. After 5 h the reaction mixture was allowed to cool, treated with saturated aqueous ammonium chloride and extracted with diethyl ether. The combined organic extracts were dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to leave a residue (14.5 g). This residue was flash chromatographed over silica gel (eluted with dichloromethane/diethyl ether 4:1) to give the desired product (2.53 g, 32%) m/z, 316.8 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH2:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)[CH3:11]>>[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)=[CH:14][CH:13]=1)[CH3:11]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: COc1cncc(Br)c1
Product: CCc1ccc(-c2cncc(OC)c2)cc1

Procedure:
5.0 g (27 mmol) of 3-bromo-5-methoxypyridine and 4.8 g (32 mmol, 1.2 eq.) of 4-ethylphenylboronic acid were reacted according to General Method 1A. Yield: 3.0 g (53% of theory)
Reaction SMILES: O.[NH2:2][NH2:3].Cl.[CH3:5][C:6]1[C:7]([O:9][C:10](=O)[C:11]=1[CH3:12])=[O:8]>O>[OH:8][C:7]1[N:2]=[N:3][C:10]([OH:9])=[C:11]([CH3:12])[C:6]=1[CH3:5]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: NN
Agent: Cl
Solvent: O
Product: Cc1c(O)nnc(O)c1C

Procedure:
50 ml of purified water was added to 3.4 ml(0.07 mol) of hydrazine monohydrate and then 14 ml(0.14 mol) of conc. hydrochloric acid was added dropwise thereto. Then, the reaction solution was warmed to boil. When the reaction mixture begins to reflux, 8.83 g(0.07 mol) of 2,3-dimethylmaleic acid anhydride was added thereto. The reaction solution was continuously refluxed for 3 hours and then cooled. The precipitated white crystal was filtered, washed with purified water, dissolved in boiling purified water to remove insoluble material and then recrystallized to obtain the title compound as an amorphous white crystal.
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1>>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:18][CH:19]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Product: CC(C)(C)c1ccc(N2CCC3(CCC4(CC3)OCCO4)C2=O)cc1

Procedure:
The title compound was prepared in analogy to example 336, step 1 from 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (described in example 133, step 3) and 1-bromo-4-tert-butyl-benzene. White solid (84%). MS (m/e): 344.2 [MH+].