Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:12])[NH:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.I[CH3:14]>CCCCCC.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3]([O:12][CH3:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CI
Reactant: O=c1[nH]cc(C(F)(F)F)cc1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Product: COc1ncc(C(F)(F)F)cc1Br
Yield: 42.3 %

Procedure:
To a suspension of 3-bromo-5-trifluoromethyl-2(1H)-pyridone (2.0 g, 8.26 mmol) and silver carbonate (2.32 g, 8.4 mmol) in hexane (50 mL) was added iodomethane (1.05 mL, 16.8 mmol) and the resulting mixture heated at reflux for 16 hrs. The suspension was cooled, and filtered, and the filtrate concentrated in vacuo. The residue was purified by silica chromatography to give the product as an oil (893 mg, 3.49 mmol, 42% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1=[N:8][CH:9]=[C:10]([O:12][CH2:13][C:14]([O:18][CH3:19])([CH3:17])[CH2:15]I)[CH:11]=[C:6]1[C:5]2=[O:24].[CH3:25][Mg]Cl.[Li+].[B-](CC)(CC)CC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1=[N:8][CH:9]=[C:10]([O:12][CH2:13][C:14]([O:18][CH3:19])([CH3:17])[CH3:15])[CH:11]=[C:6]1[C:5]2([CH3:25])[OH:24]
Reactant: COC(C)(CI)COc1cnc2oc3ccc(Br)cc3c(=O)c2c1
Reactant: C[Mg]Cl
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(C)(C)COc1cnc2c(c1)C(C)(O)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7-bromo-3-(3-iodo-2-methoxy-2-methylpropoxy)-5H-chromeno[2,3-b]pyridin-5-one (4.10 g, 8.13 mmol) in 100 mL THF was cooled to −40° C. and was treated with methylmagnesium chloride (5.42 mL, 16.27 mmol). After stirring for two hours, the reaction mixture was allowed to warm to room temperature and superhydride (40.7 mL, 40.7 mmol) was added. After stirring for an additional 2 hours the reaction mixture was cooled to 0° C. and was quenched with MeOH. The reaction mixture was poured into saturated NH4Cl solution and was extracted with EtOAc. The organics were washed with water, brine, dried over MgSO4 and concentrated yielding 7-bromo-3-(2-methoxy-2-methylpropoxy)-5-methyl-5H-chromeno[2,3-b]pyridin-5-ol.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:10]1[CH:11]=[N+:12]([O-:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=1)[CH3:9])(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[O-:20][N+:12]1[C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=[C:10]([C@H:8]([NH2:7])[CH3:9])[CH:11]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)[n+]([O-])c1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Reaction time: 4 h
Yield: 106.4 %

Procedure:
To a solution of tert-butyl{(1R)-1-[1-oxido-6-(trifluoromethyl)-3-pyridinyl]ethyl}carbamate (140 mg, 0.457 mmol) in dioxane (2 mL) was added hydrogen chloride (4.0 M in dioxane; 0.343 mL, 1.371 mmol). The reaction mixture was stirred for 4 h. The reaction mixture was concentrated to dryness to give the hydrochloride salt of the title compound (118 mg). MS 207.1 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([C:25]([F:24])([F:35])[F:36])=[CH:27][CH:28]=3)[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)c3ccc(C(F)(F)F)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.45 g, 1.3 mmol) in acetonitrile (10 mL), was added 4-trifluoromethyl-benzoyl chloride (0.30 mL, 2.0 mmol) and N,N-diisopropyl ethylamine (0.58 mL, 3.3 mmol). The mixture was stirred at room temp overnight. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-4-trifluoromethyl-benzamide as a white solid (420 mg, 67% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.46 min (97.2%); mp, 253-255° C.; 1HNMR (DMSO-d6) 2.18-2.24 (m, 1H, CHH), 2.59-2.94 (m, 6H, CHCH2, CH3), 4.94-5.11 (m, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 7.36-8.13 (m, 7H, Ar), 9.16 (t, J=5 Hz, 1H, CH2NH), 11.06 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.82, 23.28, 30.60, 42.31, 56.56, 117.68, 124.28, 125.39, 125.44, 125.57, 125.74, 128.16, 130.99, 131.41, 133.98, 137.96, 140.45, 148.50, 154.89, 161.10, 165.12, 169.54, 172.63. LCMS MH=473; Anal Calcd For C23H19N4O4F3+0.5H2O: C, 57.38; H, 4.19; N, 11.64; F, 11.84. Found: C, 57.01; H, 4.05; N, 11.53; F, 11.56.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH2:15].[Cl:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH:15][CH2:23][C:21]1[S:22][C:18]([Cl:17])=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: CC(CN)Oc1ccc2ccccc2c1Cl
Product: CC(CNCc1ccc(Cl)s1)Oc1ccc2ccccc2c1Cl
Yield: 69 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)oxy]propan-1-amine and 5-chlorothiophen-2-carbaldehyde in 69% yield as a yellow oil.
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][N:9]=1)[CH3:7])(=O)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C.O>[N:15]([CH:6]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][N:9]=1)[CH3:7])=[N+:16]=[N-:17]
Reactant: CC(OS(C)(=O)=O)c1cc(Br)ccn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 1-(4-bromopyridin-2-yl)ethyl methanesulfonate (4.68 g, 16.71 mmol) in anhydrous DMF (45 mL) DMF was added sodium azide (2.17 g, 33.41 mmol) and stirred at room temperature for 2 hours. The reaction was then diluted with 80 mL of water, then extracted with EtOAc (2×75 mL). The organic extracts were combined, washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated to give the crude product which was used directly without further purification. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=5.2 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J=5.2 Hz, 1H), 4.65 (q, J=6.8 Hz, 1H), 1.60 (dd, J=6.8, 0.8 Hz, 3H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)[C@H:10]1[CH3:26])(C(C)(C)C)(C)C.C1COCC1.Cl.C(=O)([O-])O.[Na+]>CO>[Cl:25][C:19]1[CH:18]=[C:17]([N:11]2[C@@H:10]([CH3:26])[C@H:9]([OH:8])[C:13]3([CH2:15][CH2:14]3)[C:12]2=[O:16])[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: C[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1[C@H](O)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 4-[(6S,7R)-7-(tert-butyldimethylsilyloxy)-6-methyl-4-oxo-5-azaspiro[2.4]hept-5-yl]-2-chlorobenzonitrile (65.7 mg) in a mixed solvent of THF (6 mL) and methanol (6 mL) was added 6 mol/L hydrochloric acid (4.0 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and recrystallized from hexane-ethyl acetate to give the title compound as a colorless solid (yield: 42.0 mg, 90%).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[C:14]([C:15]2[N:16]=[C:17]([S:20][C:21]3[C@H:27]([CH3:28])[C@H:26]4[N:23]([C:24](=[O:36])[C@@H:25]4[C@H:29]([O:31][Si](C)(C)C)[CH3:30])[C:22]=3[C:37]([O:39]CC=C)=[O:38])[S:18][CH:19]=2)=[CH:13][CH2:12][N:11]1[CH3:43])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[OH:31][C@@H:29]([C@H:25]1[C:24](=[O:36])[N:23]2[C@@H:26]1[C@@H:27]([CH3:28])[C:21]([S:20][C:17]1[S:18][CH:19]=[C:15]([C:14]3[C@H:10]([CH2:9][OH:8])[N:11]([CH3:43])[CH2:12][CH:13]=3)[N:16]=1)=[C:22]2[C:37]([OH:39])=[O:38])[CH3:30]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C)[C@H]3CO[Si](C)(C)C(C)(C)C)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(Sc3nc(C4=CCN(C)[C@H]4CO)cs3)[C@H](C)[C@H]12
Reaction time: 1 h

Procedure:
A solution of allyl (4R,5S,6S)-3-({4-[(2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methyl-2,5-dihydro-1H-pyrrol-3-yl]-1,3-thiazol-2-yl}sulfanyl)-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(106 mg, 0.16 mmol) in THF (2.7 ml) was cooled at 0° C. and to the solution were added acetic acid (0.073 ml, 1.28 mmol) and tetrabutylammonium fluoride in THF (1M, 0.64 ml, 0.64 mmol). The solution was stirred at the same temperature for 1 hour and then was allowed to stand in a refrigerator for 63 hours. To the reaction mixture was added water, and the solution was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography and then was subjected to de-allyl reaction in the same manner as Example 1.c) to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-({4-[(2R)-2-hydroxymethyl-1-methyl-2,5-dihydro-1H-pyrrol-3-yl]-1,3-thiazol-2-yl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([S:8][C:9]1[N:10]=[C:11]([C:15]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[C:17](=[O:25])[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(SCc2ccccc2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(SCc3ccccc3)n2)sc2ccccc12
Yield: 39.4 %

Procedure:
2-Benzylthio-6-cyanopyridine (1.63 g, 7.22 mmol) and methyl thiosalicylate (1.21 g, 7.22 mmol) were dissolved in toluene (30 ml), and triethylamine (1.52 ml, 10.8 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs. The solvent was evaporated and the residue was recrystallized from ethanol to give the titled compound (1.03 g, 44%) as white crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([CH3:17])=[C:13]([CH3:16])[N+:14]=2[O-])=[CH:6][CH:5]=1.ClCC1C=[C:23]([CH3:25])[O:22]N=1.C([O:30]C)(C)(C)C>[Zn]>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([CH3:17])=[C:13]([C:16]([O:22][CH2:23][CH3:25])=[O:30])[N:14]=2)=[CH:6][CH:5]=1
Reactant: COC(C)(C)C
Reactant: COc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Reactant: Cc1cc(CCl)no1
Agent: Cl
Agent: [Zn]
Product: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1C
Yield: 61 %

Procedure:
2-(4-Methoxyphenyl)-4-carbethoxy-5-methyloxazole was prepared in 61% yield by zinc dust reduction of the compound of part (a) in accordance with the procedure of Example 89, part (b), and obtained as a crystalline material, m.p. 74°-76° C. (from methyl t-butyl ether).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16]([N:18]1[CH2:28][CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].I[CH3:30]>O1CCCC1>[C:11]([O:15][C:16]([N:18]1[CH2:28][CH2:27][CH2:26][C:20]([CH3:30])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19]1)=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
Potassium bis(trimethylsilyl)amide (1200 ml, 0.5M in toluene, 0.6 mol) was added to a 3-necked 3-l flask equipped with an overhead stirrer, followed by tetrahydrofuran (90 ml) and the solution was cooled to −78° C. Ethyl N-(t-butyloxycarbonyl)nipecotate (100 g, 0.39 mol) in tetrahydrofuran (90 ml) was added dropwise and the resulting solution allowed to age for 15 minutes. Iodomethane (37.4 ml, 85.2 g, 0.6 mol) was added dropwise to the stirred solution keeping the temperature below −70° C. The resulting mixture was stirred at room temperature overnight and was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried (sodium sulphate) and evaporated to give a yellow oil. This was purified on a plug of silica using dichloromethane as eluant to afford the product (94 g, 90%) as a pale yellow oil.
Reaction SMILES: [N:1]([CH2:4][CH3:5])=[C:2]=[O:3].[F:6][C:7]([F:25])([F:24])[C:8]1[CH:9]=[C:10]([S:14]([N:17]2[CH2:21][CH2:20][C@H:19]([O:22][NH2:23])[CH2:18]2)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:4]([NH:1][C:2]([NH:23][O:22][C@H:19]1[CH2:20][CH2:21][N:17]([S:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:25])([F:6])[F:24])[CH:9]=2)(=[O:15])=[O:16])[CH2:18]1)=[O:3])[CH3:5]
Reactant: CCN=C=O
Reactant: NO[C@H]1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCNC(=O)NO[C@H]1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.7 %

Procedure:
Isocyanatoethane (36.0 mg, 0.5 mmol) was added to a solution of (S)—O-(1-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidin-3-yl)hydroxyl amine (155 mg, 0.5 mmol) and pyridine (119 mg, 1.5 mmol) in CH2Cl2 (8 ml), and the whole was stirred at room temperature for 17 hours. The reaction mixture was washed with aqueous 0.1 N HCl solution (10 ml), H2O (20 ml×3) and brine (20 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 60/40) to give (S)-1-ethyl-3-(1-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidin-3-yloxy)urea (150 mg, 64%) as pale yellow oil: LCMS: 382 [M+1]+. 1H NMR (DMSO-d6) δ: 0.95-1.00 (3H, t), 1.74-1.84 (1H, M), 2.05-2.06 (1H, m), 2.99-3.04 (2H, m), 3.15-3.31 (3H, m), 3.50-3.54 (1H, d), 4.21 (1H, s), 6.66-6.70 (1H, t), 7.84-7.89 (1H, t), 8.01 (1H, s), 8.07-8.14 (1H, t), 8.92 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2C(=O)[C:13]([CH3:17])([CH3:16])[C:12](=O)[NH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].P(Cl)(=O)([O:32][CH3:33])OC.[C:36]([NH:39][NH2:40])(=O)[CH3:37]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:33](=[O:32])[C:13]([CH3:16])([CH3:17])[C:12]3=[N:40][N:39]=[C:36]([CH3:37])[N:11]3[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[CH:6][CH:7]=1
Reactant: COP(=O)(Cl)OC
Reactant: CC(=O)NN
Reactant: CC1(C)C(=O)Nc2ccccc2N(c2ccc(Cl)cc2)C1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
To a solution of 1-(4-chlorophenyl)-3,3-dimethyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (100 mg, 0.32 mmol) in THF (10 mL) was added a solution of t-BuOK (35.8 mg, 0.32 mmol) dropwise at −78° C. over 10 min. The solution was slowly warmed up to 0° C. in 30 min and recooled to −78° C. for the addition of dimethyl phosphorochloridate (55 mg, 0.38 mmol). The mixture was warmed up to 0° C. over 30 min and stirred for 1 hour at room temperature. The solution was cooled to −78° C. and a solution of acetohydrazide (28 mg, 0.38 mmol) in THF (5 mL) was added. The mixture was heated to reflux for 3 hours. The crude solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were dried over Na2SO4, concentrated in vacuo and the residue was purified by column chromatography (silica-gel, DCM: methanol=20:1) to give 6-(4-chlorophenyl)-1,4,4-trimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one as a white solid (51 mg, yield 44%) LRMS (M+H+) m/z: calcd 352.11. found 352.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH:3]=O.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[OH:16].CNC.[H][H]>[Ni].CO.O>[CH3:8][C:9]1[CH:14]=[C:13]([CH2:3][C:2]([CH3:1])([CH3:7])[CH2:5][OH:6])[CH:12]=[C:11]([CH3:15])[C:10]=1[OH:16]
Reactant: CC(C)(C=O)CO
Reactant: Cc1cccc(C)c1O
Reactant: [H][H]
Agent: [Ni]
Agent: CNC
Solvent: CO
Solvent: O
Product: Cc1cc(CC(C)(C)CO)cc(C)c1O
Yield: 92 %

Procedure:
125 g (1 mol) of 80% strength aqueous 2,2-dimethyl-3-hydroxypropanal (crude mixture from the synthesis, reduced to a water content of 20%. by distillation), 109 g (0.9 mol) of 2,6-dimethylphenol, 12 g (0.11 mol) of 40% strength aqueous dimethylamine and 700 g of methanol are reacted in a stirred autoclave at 180° C. under autogenous pressure of 20-30 bar for 10 h. After the autoclave has cooled and the pressure has been released, 19 g of Raney Ni (0.02 parts based on complete mixture) are added to the reaction mixture and hydrogenation is carried out at 80° C. under 80 bar of hydrogen for 5 h. Workup of the mixture by distillation yields 174 g (92%) of 3-(3,5-dimethyl-4-hydroxyphenyl)-2,2-dimethylpropanol (boiling point 172°-174° C.; melting point 133°-134° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH3:8].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[N+](C1C=CC([O:28][C:29]([C:31]2[CH:32]=[CH:33][C:34]([O:46][CH3:47])=[C:35]3[O:39][C:38]([S:40](=[O:45])(=[O:44])[N:41]([CH3:43])[CH3:42])=[CH:37][C:36]=23)=O)=CC=1)([O-])=O.O>CN(C)C=O>[CH3:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C:29]([C:31]1[CH:32]=[CH:33][C:34]([O:46][CH3:47])=[C:35]2[O:39][C:38]([S:40](=[O:44])(=[O:45])[N:41]([CH3:43])[CH3:42])=[CH:37][C:36]=12)=[O:28]
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(S(=O)(=O)N(C)C)oc12
Reactant: Cc1cnccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2ccncc2C)c2cc(S(=O)(=O)N(C)C)oc12
Reaction time: 0.08 h
Yield: 81 %

Procedure:
To a stirred solution of 4-amino-3-methylpyridine (200 mg) in dimethylformamide (8 ml) under an atmosphere of nitrogen at 0° C. was added sodium hexamethyldisilazide (1.0M solution in tetrahydrofuran, 1.9 ml). The reaction mixture was stirred at this temperature for 5 minutes. 2-Dimethylsulfamyl-7-methoxy-benzofuran-4-carboxylic acid 4-nitrophenyl ester (400 mg) was then added and stirring continued for 30 minutes. Water (10 ml) was added and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 ml), washed with water (3×50 ml) and washed with brine (50 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography eluting with 10% methanol in ethyl acetate afforded the title compound as a white solid (0.3 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].[C:21]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)#[N:22].CCN(C(C)C)C(C)C.C(OC1C=CC(/C=C2/C(=O)N(CCNC(=O)C)C(=O)S/2)=CC=1)C>>[C:21]([C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:1][CH2:2][CH2:3][N:4]2[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=3)/[S:6][C:5]2=[O:20])(=[O:31])=[O:30])=[CH:27][CH:28]=1)#[N:22]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCNC(C)=O)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNS(=O)(=O)c3ccc(C#N)cc3)C2=O)cc1

Procedure:
The title compound 27b was prepared from compound 76 (101 mg, 0.25 mmol), 4-cyano-benzenesulfonyl chloride (55 mg, 0.28 mmol) and DIPEA (131 μL, 0.75 mmol) in a manner similar to that described for 25a in 92.0% (105 mg) yield as a light-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17]>O1CCCC1.CN(C)C=O>[NH2:1][C:2]1[N:6]([CH2:16][CH3:17])[CH:5]=[N:4][C:3]=1[C:7]#[N:8]
Reactant: CCI
Reactant: N#Cc1nc[nH]c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1cnc(C#N)c1N
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution/suspension of 5-amino-1H-imidazole-4-carbonitrile (2.16 g) in tetrahydrofuran/N,N-dimethylformamide under an atmosphere of nitrogen was added potassium carbonate (3.3 g) and iodoethane (1.9 mL). The reaction mixture was stirred at room temperature for 60 hours, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 2-5% methanol in dichloromethane afforded the title compound as an off-white solid (0.60 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.C([N:18]([CH2:21]C)CC)C.[C:23]([S:26]([OH:29])(=[O:28])=[O:27])([NH2:25])=[NH:24]>CN(C=O)C>[S:26]([OH:29])([OH:28])=[O:27].[NH2:24][N:18]=[CH:21][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3][CH2:2]1.[C:11]([O:10][C:9](=[O:15])[NH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH:23]=[N:25][NH2:18])[CH2:2][CH2:3]1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CCN(CC)CC
Reactant: N=C(N)S(=O)(=O)O
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CCN(C=NN)CC1
Product: O=S(O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 130 g of 1,1-dimethylethyl (4piperidinylmethyl)-carbamate in 1300 ml of DMF is treated with 138 ml of triethylamine and 61.8 g of formamidinesulfonic acid and the mixture is stirred at room temperature overnight. The precipitated material is filtered, suspended in 500 ml of ethanol, again filtered off and dried. There are obtained 65.6 g of tert-butyl 1-(aminoimino-methyl)-piperidin-4-ylmethylcarbamate hemisulfite, MS (ISP): 257.4 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:16][CH2:17]/[CH:18]=[CH:19]/[C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[O:21])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(C1C2C(=CC=CC=2)NC=1)(=O)CCCCCC.Br[CH2:49][CH2:50][CH2:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=1)=[O:53].BrCCCC([O-])=O>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([O:16][CH2:17]/[CH:18]=[CH:19]/[C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:49][CH2:50][CH2:51][C:52]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=3)=[O:53])[CH:23]=2)=[O:21])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCC(OC/C=C/C(=O)c1c[nH]c2ccccc12)c1ccc(CC(C)C)cc1
Reactant: COc1ccc(COC(=O)CCCBr)cc1
Agent: CCCCCCC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])CCCBr
Product: CCCCC(OC/C=C/C(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12)c1ccc(CC(C)C)cc1

Procedure:
The procedure of Ex. 1 was repeated except that (E)-3-[4-[1-(4-isobutylphenyl)pentyloxy]-2-butenoyl]indole obtained in Step 4 of Pre. Ex. 19 was used in place of 3-heptanoylindole, and 4-methoxybenzyl 4-bromobutyrate obtained in Step 5 of Pre. Ex. 19 was used in place of 4-bromobutyrate to give 4-methoxybenzyl (E)-4-[3-[4-[1-(4-isobutylphenyl)pentyloxy]-2-butenoyl]1-indolyl]butyrate as an oil.