Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:18](=[O:32])[NH:17]2)=[CH:9][CH:8]=1)[CH3:2].[H-].[Na+].I[CH3:45]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:45])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc4ccccc4c3)C(=O)N2)cc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc4ccccc4c3)C(=O)N2C)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of a diasteriomeric mixture of 2-methyl-3-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (0.275 g, 0.498 mmol) in DMF (7 mL) is treated with NaH (60% oil suspension, 0.030 g, 0.750 mmol) and stirred at room temperature under N2 for 30 minutes. The reaction is cooled to 0° C. and treated with iodomethane (0.141 g, 0.996 mmol) and then warmed to room temperature and stirred for 3 hours. The reaction is quenched with 1 N HCl (5 mL) and worked up extractively with Et2O and water. The organic layer is dried and the solvent removed in vacuo to afford crude product that is purified by flash chromatography using 4:1 hexanes:acetone to afford 0.268 g (95%) 2-methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester. The diasteriomeric products are separated by chiral HPLC (8×32 cm Chiralpak AD, 100% IPA, 350 mL/min, 270 nm, to give products in>99% de 1H NMR. Rf=0.35 (1:1 acetone:hexanes). MS (ES+) Calc'd for C35H39N2O5 (M+1) 567. Found m/z 567 (100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH:16]([C:19]1[CH:20]=[CH:21][C:22]([O:37][CH3:38])=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[CH2:35][NH2:36])[CH:24]=1)([CH3:18])[CH3:17].[BH3-]C#N.[Na+].O>CO.C(O)(=O)C>[CH:16]([C:19]1[CH:20]=[CH:21][C:22]([O:37][CH3:38])=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=2[CH2:35][NH:36][CH2:7][C:6]2[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:24]=1)([CH3:18])[CH3:17]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Reactant: O=Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-nitro-5-(trifluoromethyl)benzaldehyde (366 mg, 1.67 mmol) in MeOH (4 mL) was added a solution of 1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine (270 mg, 0.84 mmol) in MeOH (4 mL) followed by addition of NaCNBH3 (105 mg, 1.67 mmol) and one drop of acetic acid. The reaction was stirred for 24 hours at room temperature and then poured into H2O (30 mL). The mixture was extracted with EtOAc (60 mL), and the organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 2% to 25% EtOAc/hexanes afforded {[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-nitro-5-(trifluoromethyl)benzyl]amine as a yellow oil. Rf=0.45 (15% EtOAc/hexanes). LCMS=527.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 8.33 (s, 1H), 8.27 (s, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.22 (dd, J=8.5 Hz, 2.0 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 3.67-3.78 (m, 4H), 3.70 (s, 3H), 2.87 (m, 1H), 1.25 (d, J=7.0 Hz, 6H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([Cl:6])[CH:4]=[CH2:5].[C:7](#[N:10])[CH:8]=[CH2:9].S(OOS([O-])(=O)=O)([O-])(=O)=[O:12].[K+].[K+]>O>[C:7](#[N:10])[CH:8]=[CH2:9].[CH2:3]([OH:12])[CH:4]=[CH2:5].[CH2:3]([Cl:6])[CH:4]=[CH2:5]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: C=CCCl
Solvent: C=CC#N
Solvent: O
Product: C=CCO
Reaction time: 6.5 h

Procedure:
About 10 parts by weight of fine granular silica, 2.5 parts by weight of sodium hydroxide flakes and 2 parts by weight of water are mixed then heated at 90 degrees to 100 degrees C. until the water evaporates, thereby producing an activated silica. 30 parts by weight of allyl chloride, 3 parts by weight of acrylonitrile, 12 parts by weight of water and 0.2 parts by weight of potassium persulfate are mixed then agitated at a temperature just below the boiling temperature of the reactants at ambient pressure for 1 to 12 hours, thereby producing a white, solid poly (allyl chloride allyl alcohol acrylonitrile) copolymer.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.S([O-])([O-])(=O)=O.[Mg+2].[Cl-].[C:18]([O:22][C:23](=[O:26])[CH2:24][Zn+])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.C(OCC)(=O)C>[CH2:18]([O:22][C:23](=[O:26])[CH:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)[CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH3:19]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 65 %

Procedure:
To a solution/suspension of 5-aminoindazole (1.01 g, 7.6 mmol) in tetrahydrofuran (20 mL) was added ethyl glyoxlate solution (ca. 50% in toluene, 1.7 mL, 1.1 equiv) in one portion followed by magnesium sulfate (4.6 g). The mixture was stirred at room temperature overnight (23 h) and then filtered and concentrated in vacuo. The resulting crude imine intermediate (1.3 g, 6 mmol) was dried by azeotroping with anhydrous benzene and further dried under high vacuum. The residue was then dissolved in tetrahydrofuran (20 mL) and cooled at 0° C. A solution of 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in ether, 24 mL, 2 equiv) was then slowly added. After stirring at 0° C. for 1 h, the mixture was stored at 4° C. overnight. The mixture was then diluted with ethyl acetate and quenched with half-saturated ammonium chloride solution along with a minimum amount of 0.5 N HCl to dissolve the precipitated solids. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel, eluting with 10% methanol in methylene chloride, to afford the desired product (1.3 g, 65%) as a tan oil. 1H-NMR (400 MHz, CDCl3) δ 7.89 (1H, s), 7.40–7.27 (1H, m), 6.98–6.77 (2H, m), 4.42–4.35 (1H, m), 4.30–4.12 (3H, m), 2.80 (2H, d, J=4.4 Hz ), 1.43 (9H, s), 1.27–1.17 (4H, m). Mass spec.: 356.24 (M+Na)+, 278.23 (M−tBu)+, tR=1.287 min.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5(CCCCC)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:20][C:19]=4[F:35])(O)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:36]1(C)[CH:41]=[CH:40]C(S(O)(=O)=O)=[CH:38][CH:37]=1.C1(C)C=CC=CC=1>O>[F:35][C:19]1[CH:20]=[C:21]([CH:24]2[CH2:25][CH2:26][CH:27]([CH2:38][CH2:37][CH2:36][CH2:41][CH3:40])[CH2:28][CH2:29]2)[CH:22]=[CH:23][C:18]=1[C:14]1[CH2:13][CH2:12][CH:11]([CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH2:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCC1(c2ccc(C3(O)CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CCC(c2ccc(C3=CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1
Temperature: 30 °C
Yield: 537.4 %

Procedure:
The compound (3) (108.6 g), p-toluenesulfonic acid (4.02 g) and toluene (500 ml) were mixed, and the mixture was heated under reflux for 1.5 hours while the water being distilled was removed. The reaction mixture was cooled to 30° C., and then water (1,000 ml) and toluene (1,800 ml) were added and mixed with it. The mixture was then allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent of the solution was distilled off under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=7:3 by volume) as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from heptane and dried, giving 58.8 g of 8-{4-[2-fluoro-4-(4-pentyl-cyclohexyl)-phenyl]-cyclohex-3-enyl}-1,4-dioxa-spiro[4,5] decane (4). The yield based on the compound (1) was 53.4%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.[C:13](C1NC=CN=1)([C:15]1N[CH:17]=[CH:18][N:19]=1)=[O:14].N1CCOCC1>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([N:19]3[CH2:15][CH2:13][O:14][CH2:17][CH2:18]3)=[O:12])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Solvent: ClCCl
Solvent: C1COCCN1
Product: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
Indole-6-carboxylic acid (0.60 g, 3.7 mmol) was dissolved in DCM (15 mL) and carbonyl diimidazole (0.63 g, 3.9 mmol) was added and the reaction mixture was refluxed under N2 for 30 min. The mixture was allowed to cool to room temperature before morpholine (0.39 g, 4.5 mmol) was added and the reaction mixture was refluxed for 16 hours. The mixture was allowed to cool to room temperature before it was washed in seqence with HCl (50 mL, 1 N in water), NaOH (50 mL, 1 N in water) and brine (50 mL). The organic phase was dried with MgSO4, and the solvent was removed in vacuo to give 0.74 g of (1H-indol-6-yl)-morpholin-4-yl-methanone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:14]1([C:20]2[CH:24]=[C:23]([CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([CH2:32][NH2:33])[CH2:28][CH2:27]3)[O:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7]([NH:33][CH2:32][CH:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:23]2[O:22][N:21]=[C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:24]=2)[CH2:31][CH2:30]1)=[O:9]
Reactant: CCOc1ncc(N)cc1C(=O)O
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Product: CCOc1ncc(N)cc1C(=O)NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1

Procedure:
According to the same procedure described in Example 225, using the compound prepared in Example 288 instead of 4-amino-5-cyano-6-ethoxypicolinic acid, and using the compound prepared in Example 9 instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, the title compound having the following physical data was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:15](Br)=[N:16][C:17]([CH3:21])=[CH:18][C:19]=2Br)=[O:12])[CH2:6][CH2:5]1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:16][C:17]([CH3:21])=[CH:18][C:19]=2[N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:12])[CH2:6][CH2:5]1
Reactant: Cc1cc(Br)c(NC(=O)CN2CCN(CCO)CC2)c(Br)n1
Reactant: C1CCNC1
Product: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCCC2)n1

Procedure:
2-[4-(2-Hydroxyethyl)piperazin-1-yl]-N-[2,4-dibromo-6-methyl-3-pyridyl]acetamide (1.00 g, 2.29 mmol) was dissolved in pyrrolidine (10 mL), and the solution was subjected to reflux for 4 days. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to separation through silica gel column chromatography (developer: hexane:acetone=2:1), to thereby yield a crude product of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methyl-3-pyridyl]acetamide (1.22 g) as a brown foamed substance. The crude product was dissolved in pyridine (20 mL), and acetic anhydride (10 mL) was added thereto under cooling with ice, followed by stirrng for 14 hours at room temperature. The reaction mixture was concentrated under reduced pressure. Toluene (70 mL) was added to the residue and then evaporated three times, followed by purification through silica gel column chromatography (developer: chloroform:methanol=20:1→chloroform: ammonia-saturated methanol=50:1→chloroform:ammonia-saturated methanol=20:1), to thereby yield a brown oil (1.05 g). The oil was dissolved in ammonia-saturated methanol (30 mL), and the solution was stirred for 14 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (developer: chloroform:ammonia-saturated methanol=100:1→chloroform:ammonia-saturated methanol=20:1), to thereby yield 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methyl-3-pyridyl]acetamide (911 mg, yield 95%) as a pale brown foamed substance.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[C:32]=1[OH:33])[CH:28]=O)[CH3:23].[NH2:37][C:38]([NH2:40])=[O:39].Cl>CCO>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH:28]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:8][CH:9]=3)[NH:40][C:38](=[O:39])[NH:37]2)[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[C:32]=1[OH:33])[CH3:23]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccc(N2CCOCC2)cc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(N4CCOCC4)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 12.9 %

Procedure:
A mixture of 1-(4-morpholinophenyl)-2-phenylethanone (Intermediate 25) (280 mg, 1.00 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (175 mg, 0.83 mmol), urea (179 mg, 2.99 mmol), and concentrated HCl solution (0.07 mL, 0.83 mmol) in EtOH (5 mL) was refluxed for 48 h. The mixture was evaporated in vacuo, and the residue was purified by preparative HPLC to give Compound 56 (55.29 mg, yield 13%) as a solid. 1H NMR (CD3OD 300 MHz): δ 7.62 (d, J=2.1 Hz, 1H), 7.20-7.15 (m, 3H), 7.10-7.04 (m, 3H), 6.92-6.85 (m, 4H), 5.30 (s, 1H), 4.12-4.02 (m, 2H), 3.81 (t, J=4.8 Hz, 4H), 3.15 (t, J=4.8 Hz, 4H), 1.41 (t, J=6.9 Hz, 3H); MS (ESI): m/z 517.0 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]/[CH:19]=[C:20]3\[C:21](=[O:32])[NH:22][C:23](=[O:31])[C:24]4[C:29]\3=[CH:28][C:27]([I:30])=[CH:26][CH:25]=4)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.BrC1C=C2C(=CC=1)[C:41](=[O:45])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[I:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:31])[NH:22][C:21](=[O:32])/[C:20]/2=[CH:19]/[O:45][CH3:41].[CH3:33][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1
Reactant: CN(C)CCCN1CCC(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Product: CN(C)CCCN1CCC(c2ccc(N)cc2)CC1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, 0.079 g (73.1% yield) of greenish tan solid is obtained from 0.064 g (0.19 mmol) of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and 0.061 g (0.23 mmol) of (4-{1-[3-(dimethylamino)propyl]piperidin-4-yl}phenyl)amine: mp 139-140° C.; MS (ESI) m/z 559.0 (M+H)+1
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][SiH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH2:3]1.[Mg].P(OCC)(OCC)(OCC)=O.Br[CH2:26][CH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>[Cu]I.C1COCC1>[CH2:8]([Si@H:5]1[CH2:6][CH2:7][C@H:2]([CH2:26][CH2:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=4)=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:3][CH2:4]1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC[SiH]1CCC(Br)CC1
Reactant: Fc1ccc(-c2ccc([C@H]3CC[C@H](CCBr)CC3)cc2)cc1
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)cc4)cc3)CC2)CC1

Procedure:
24.9 g (0.1 mol) of 1-bromo-4-n-pentyl-4-silacyclohexane was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 36.1 g (0.1 mol) of 4-(trans-4-(2-bromoethyl)cyclohexyl)-4'-fluorobiphenyl. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl)-4'-fluorobiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 30.5 g (yield 67.6%) of the trans isomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][S:10][C:11]2[NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)[CH:6]=[CH:7][CH:8]=1.[Se](=O)=[O:21].OO.O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][S:10]([C:11]2[NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CSc2nc3cnccc3[nH]2)c1
Reactant: O=[Se]=O
Agent: OO
Solvent: O
Solvent: CO
Product: COc1cccc(CS(=O)c2nc3cnccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[[(3-Methoxyphenyl)methyl]thio]-1H-imidazo[4,5-c]pyridine (9.88 g, 0.036 mol) was dissolved in 130 mL of methanol by heating. An oxidizing solution was prepared by dissolving 4.0 g (0.036 mol) of selenium dioxide in 150 mL of methanol with heating followed by the addition of 4.07 g (0.036 mol) of 30% hydrogen peroxide and 2.5 mL of water. The oxidizing solution was cooled to room temperature and was added dropwise to the sulfide solution. The reaction mixture was stirred overnight. The precipitate which had formed was collected on a filter and rinsed with petroleum ether giving 4.68 g of product. An analytical sample (m.p. 176°-179° C.) was obtained by recrystallization from ethanol.
Reaction SMILES: [Cl:1][CH:2]([C:14](=[O:16])[CH3:15])[CH2:3][S:4][CH2:5][CH2:6][NH:7][C:8]([NH:11][C:12]#[N:13])=[N:9][CH3:10].O.[Cl:18]OC(C)(C)C.C(OCC)(=O)C>CO>[C:12]([NH:11][C:8]([NH:7][CH2:6][CH2:5][S:4][CH2:3][C:2]([Cl:18])([Cl:1])[C:14](=[O:16])[CH3:15])=[N:9][CH3:10])#[N:13]
Reactant: CN=C(NC#N)NCCSCC(Cl)C(C)=O
Reactant: CC(C)(C)OCl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN=C(NC#N)NCCSCC(Cl)(Cl)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.2 %

Procedure:
In 1 ml of methanol was dissolved 131 mg of N-[2-(2-chloro-3-oxobutylthio)]ethyl-N'-cyano-N"-methyl-guanidine, and the solution was cooled with water and 55 mg of t-butyl hypochlorite was added to the solution. The mixture was stirred at 0° C. for 1 hour and 1 ml of water and 15 ml of ethyl acetate were added to the reaction mixture. The ethyl acetate layer was recovered, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was refined by silica gel column chromatography (developing solvent: ethyl acetate/ethanol=10/1) to obtain 24 mg of a colorless oily product (the yield was 16%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:18])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:20]1[C:26](=[O:27])[NH:25][C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[O:18][CH:20]1[C:26](=[O:27])[NH:25][C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[CH2:22][CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1OCc1ccccc1
Reactant: O=C1Nc2ccccc2CCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1Nc2ccccc2CCC1Oc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1

Procedure:
A mixture of 3-benzyloxy-4-nitrophenol (2.45 g, 10 mmol), 3-bromo-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (2.4 g, 10 mmol) and potassium carbonate (3.1 g, 23 mmol) in MeCN (10 mL) is refluxed for 10 h. Upon cooling a precipitate forms. The solid is filtered, washed with water and crystallized from EtOAc to give the title compound: mp=188-189° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.Cl.[CH:23]1([CH2:26][O:27][NH2:28])[CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH:23]1([CH2:26][O:27][NH:28][C:13](=[O:15])[C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:18])[CH3:17])[CH2:25][CH2:24]1
Reactant: NOCC1CC1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)[C@H](C(=O)NOCC1CC1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 27.2 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol). DMF (0.5 mL), O-(cyclopropylmethyl)hydroxylamine hydrochloride (6.4 mg, 0.051 mmol), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (5 mg, 23%). 1H NMR (400 MHz, CD3OD) δ 0.16-0.24 (m, 2 H) 0.39-0.55 (m, 2 H) 0.93 (d, J=6.57 Hz, 3 H) 1.05 (d, J=6.32 Hz, 3 H) 1.06-1.15 (m, 1 H) 2.53 (dt, J=11.24, 6.51 Hz, 1 H) 3.55-3.73 (m, 2 H) 4.94 (d, J=11.37 Hz, 1 H) 5.07 (d, J=19.20 Hz, 1 H) 5.46 (d, J=18.44 Hz, 1 H) 7.86 (s, 1 H) 8.17 (d, J=3.28 Hz, 1 H). [M+H] calc'd for C18H21FN4O3, 361; found, 361.4.