Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][CH2:3]1.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][CH2:3]1
Reactant: CC1CNC(=O)c2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC1CNC(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methyl-3,4-dihydro-2H-isoquinolin-1-one (1. Og) (J. Med. Chem., 1988, 31, 433) in conc. sulfuric acid (5 ml) was added dropwise over 20 min to an ice cooled solution of potassium nitrate (0.678 g) in conc. sulfuric acid (5 ml). The mixture was stirred for a further 30 min with ice-cooling. The mixture was added dropwise to ice (150 g) with stirring. The precipitated solid was collected by filtration, washed with water and dried to give the sub-titl compound (0.95 g). 1H NMR δ: 1.28 (3H, d, J=6.6 Hz), 3.14-3.28 (1H, m), 3.52 (2H, m), 7.67 (1H, d, J=8.5 Hz), 8.29 (1H, s), 8.35 (1H, dd, J=2.5, 8.4 Hz) (1H, d, J=2.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:29])[CH:27]=[CH2:28]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:29][CH2:26][CH:27]=[CH2:28])=[O:10])[CH2:6]1
Reactant: C=CCN
Reactant: O=C(Cl)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Reaction time: 16 h

Procedure:
A mixture of 2 g (0.0065 mole) of 3-[2-chloro-4-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 0.9 g (0.0065 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated while stirring with 0.35 g (0.0065 mole) of 2-propenylamine. After stirring for 16 h, the reaction mixture was diluted with 100 ml of water whereupon an oil separated. The oil slowly solidified and was collected by filtration (2.3 g wet). The rose colored solid was recrystallized from benzene/ligroin yielding 1.7 g (78.1%) of beige crystals, mp 102°-104°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][CH2:33][C@H:34]1[NH:38][C:37](=[O:39])[CH2:36][CH2:35]1.O[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1>C1COCC1>[O:39]=[C:37]1[NH:38][C@H:34]([CH2:33][O:32][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[CH2:35][CH2:36]1
Reactant: Oc1cccnc1
Reactant: O=C1CC[C@@H](CO)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CC[C@@H](COc2cccnc2)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of triphenylphosphine (52.46 g, 0.20 mol) in 400 mL of anhydrous THF at 0° C. was added diethyl azodicarboxylate (31.49 mL, 0.20 mol) dropwise. The mixture was stirred at 0° C. for 30 minutes, then brought to room temperature. (S)-5(Hydroxymethyl)-2-pyrrolidinone (Aldrich Chemical Co., 15.19 g, 0.13 mol) and 3-hydroxypyridine (19.02 g, 0.20 mol) were added to the reaction vessel, and stirred for 16 hours. Solvent was removed in vacuo. The residue was diluted with CH2Cl2 and washed with 1N NaOH. After a brine wash (2×), the organic layer was dried over MgSO4. The residue was purified by silica gel flash chromatography using a gradient from 100% CHCl3 to 10% MeOH/CHCl3 (purification system was run twice), then recrystallized with ethyl acetate to give 4.0 g (16%) of the title compound as a white powder, mp.=121-122° C. TLC Rf =0.31 (10%MeOH/CHCl3). MS (DCI/NH3) m/e: 193 (M+H)+ and 210 (M+NH4)+. 1H NMR (CDCl3, 300 MHz) δ: 8.32-8.30 (m, 111), 8.27 (dd, J=4.40, 1.50 Hz, 1H), 7.25-7.16 (m, 2H), 6.17 (br s, 1H), 4.14-4.08 (m, 1H), 4.05 (dd, J=8.80, 3.70 Hz, 1H), 3.89 (dd, J=8.80, 7.70 Hz, 1H1), 2.49-2.23 (m, 3H), 1.99-1.87 (m, 1H). Anal. Calc. for C10H12N2O2 : C, 62.49; H, 6.29; N, 14.57; Found C, 62.53; H, 6.25; N, 14.71.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23](Cl)=[O:24]>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:23](=[O:24])[CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)[CH2:9][CH2:8]2
Reactant: CCCN[C@H]1CCc2cccc(OC)c2C1
Reactant: O=C(Cl)Cc1cccs1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCN(C(=O)Cc1cccs1)[C@H]1CCc2cccc(OC)c2C1

Procedure:
Synthesis worked according to the preparation of A4-1 when using 310 mg (1.4 mmol) enantiomerical pure (S)—N-(8-methoxytetralin-2-yl)-N-propylamine ((R)-A2-1: R═OMe) and 0.35 mL (2.8 mmol) 2-thienyl acetic acid chloride. Flash chromatography was done with hexane/ethyl acetate 20/1.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:8])=[C:4]([CH3:17])[CH:3]=1.[Cu](C#N)[C:19]#[N:20]>CN(C)C=O>[C:19]([C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:8])=[C:4]([CH3:17])[CH:3]=1)#[N:20]
Reactant: Cc1cc(Br)sc1C(=O)NCc1cccnc1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: Cc1cc(C#N)sc1C(=O)NCc1cccnc1
Temperature: 150 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
A mixture of 5-bromo-3-methyl-N-(pyridin-3-ylmethyl)thiophene-2-carboxamide (1.92 g, 6.17 mmol) and copper cyanide (2.21 g, 24.68 mmol) in anhydrous N,N-dimethylformamide (25 mL) was stirred under nitrogen atmosphere at 150° C. for 18 h. The reaction mixture was allowed to cool to ambient temperature, and partitioned between ethyl acetate (200 mL) and 14% aqueous ammonium hydroxide solution (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL), and combined organic layer was washed with water (2×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 7% methanol in dichloromethane to afford the title compound as an off-white solid (0.72 g, 45%): 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.57 (s, 1H), 7.71 (dd, J=7.8, 7.8 Hz, 1H), 7.39 (s, 1H), 7.30 (m, 1H), 6.31 (br s, 1H), 4.63 (d, J=5.9 Hz, 2H), 2.50 (s, 3H); MS (ES+) m/z 258.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[C:19]([NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:27][C:28]([O:30][CH3:31])=[O:29])=[N:20][CH:21]=[CH:22][CH:23]=2)[O:5][CH2:4]1.C1N=CN([C:51]([N:53]2C=N[CH:55]=[CH:54]2)=[O:52])C=1.[F:58][C:59]1[CH:66]=[CH:65]C(CN)=[CH:61][CH:60]=1>N1C=CC=CC=1.CCOC(C)=O>[F:58][C:59]1[CH:66]=[CH:65][C:55]([CH2:54][NH:53][C:51]([O:1][CH2:2][C@H:3]2[N:8]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]3[C:19]([NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[NH:27][C:28]([O:30][CH3:31])=[O:29])=[N:20][CH:21]=[CH:22][CH:23]=3)[O:5][CH2:4]2)=[O:52])=[CH:61][CH:60]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)N[C@H](C(=O)Nc1ncccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1)C(c1ccccc1)c1ccccc1
Reactant: NCc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)N[C@H](C(=O)Nc1ncccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCc2ccc(F)cc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of tert-butyl (2R,5R)-5-(hydroxymethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}pyridin-3-yl)ethyl]morpholine-4-carboxylate (1 eq) and CDI (2.05 eq.) was dissolved in dry Pyridine (0.04 M) and the resulting solution stirred under N2 at rt for 5 h and then at 49° C. for 0.5 h; then neat 4-fluorobenzylamine (6 eq.) was added and the resulting mixture further stirred at the same temperature for 12 h. The crude reaction mixture was diluted with EtOAc, washed with 5% aq. KHSO4 then sat. NaHCO3, dried over Na2SO4, filtered and concentrated. The residue was purified by automated silicagel flash chromatography system eluted with a gradient 0% to 5% MeOH in DCM, to afford title compound.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:12]([C:20]1[CH:21]=[CH:22][C:23]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:24][CH:25]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCc1ccccc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CCCCCCCCc1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (608 mg, 4 mM) and n-octylbenzene (1.77 ml, 8 mM) were dissolved in dichloroethane (8 ml), titanium tetrachloride (0.66 ml, 6 mM) was added, and reacted at room temperature for 30 minutes. Using the same procedure as in Example 1, 4'-n-octylbenzoin was obtained as crystal (810.0 mg, 62.6% yield).
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)O1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[F:19][C:14]([F:20])([O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:29]3[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=3)=[N:3]2)=[CH:8][CH:9]=1)[C:15]([F:18])([F:17])[F:16]
Reactant: FC(F)(F)C(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 120 °C
Yield: 72.7 %

Procedure:
3-Bromo-1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazole (1.5 g, 4.2 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.12 g, 5.12 mmol), Pd(PPh3)4 (0.49 g, 0.424 mmol) and K2CO3 (1.17 g, 8.52 mmol) were combined in a round bottom flask in 5:1 DME/water (22 mL), and the solution was degassed with nitrogen for 15 min. The reaction was then heated for 18 h at 120° C. The reaction mixture was cooled and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (2×50 ml). The combined organic extracts were dried over anhydrous MgSO4 and concentrated onto 8 g of Celite®. The Celite® was loaded onto a silica column and the target molecule was eluted using 0-100% EtOAc/hexanes to afford the title compound as a tan solid (1.13 g, 68%): 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.99 (d, J=8.7 Hz, 2H), 7.78 (d, J=9.1 Hz, 2H), 7.36 (d, J=9.1 Hz, 2H), 6.76 (d, J=8.7 Hz, 2H), 3.90 (s, 2H); ESIMS m/z 371.2 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[CH3:17][S:18][C:19]1[S:23][C:22]([SH:24])=[N:21][N:20]=1.N12CCCN=C1CCCC=C2>CN(C)C=O.CCOCC>[CH3:9][C:8]([C:6]1[CH:7]=[C:2]([S:24][C:22]2[S:23][C:19]([S:18][CH3:17])=[N:20][N:21]=2)[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[OH:12])([CH3:11])[CH3:10]
Reactant: CSc1nnc(S)s1
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O
Agent: C1=CN2CCCN=C2CCC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSc1nnc(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Yield: 18.1 %

Procedure:
A solution of 4-bromo-2,6-di-t-butylphenol (3.0 g, 10.5 mmol), 5-methylthio-1,3,4-thiadiazole-2-thiol (2.0 g, 12.2 mmol), and 1,8-diazabicyclo-[5.4.0]undecen-7-ene (1.8 mL, 12.0 mmol) in dimethylformamide (120 mL) is stirred at 55° to 70° C. for 48 hours. The reaction mixture is cooled and diluted with ether then washed four times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a solid residue which is crystallized from ethyl acetate/hexane yielding 2.4 g (63%) of analytically pure light brown platelets; mp 144.0°-145.0° C. The mother liquor is chromatographed on silica gel eluting with 1:9 then 2:8 ethyl acetate:hexane to yield an additional 0.7 g (18%) of 2,6-bis(1,1-dimethylethyl)-4-[[5-(methylthio)-1,3,4-thiadiazol-2-yl]thio]phenol.
Reaction SMILES: CS(Cl)(=O)=O.[NH2:6][C:7]1[S:8][CH:9]=[C:10](/[C:12](=[N:16]/[O:17][CH3:18])/[C:13]([OH:15])=O)[N:11]=1.C(N(CC)C(C)C)(C)C.[NH2:28][C@@H:29]1[C:53](=[O:54])[N:31]2[C:32]([C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=3)=[O:42])=[C:33]([C@@H:36]3[CH2:40][CH2:39][CH2:38][O:37]3)[CH2:34][S:35][C@H:30]12.N1C=CC=CC=1>CN(C=O)C>[NH2:6][C:7]1[S:8][CH:9]=[C:10](/[C:12](=[N:16]/[O:17][CH3:18])/[C:13]([NH:28][C@@H:29]2[C:53](=[O:54])[N:31]3[C:32]([C:41]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=4)=[O:42])=[C:33]([C@@H:36]4[CH2:40][CH2:39][CH2:38][O:37]4)[CH2:34][S:35][C@H:30]23)=[O:15])[N:11]=1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: COc1ccc(COC(=O)C2=C([C@@H]3CCCO3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
Methanesulphonyl chloride (203 μl, 2.62 mmol) was added to 2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid (528 mg, 2.63 mmol) and N,N-diisopropylethylamine (458 μl, 2.63 mmol) in DMF (8 ml) at -30° C. After stirring at -30±10° C. for 30 min., a solution of 4-methoxybenzyl (6R,7R)-7-amino-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (930 mg, 2.38 mmol) in DMF (5 ml) was added, followed by pyridine (213 μl, 2.63 mmol). The reaction mixture was transferred to an ice-bath and stirring continued for a further 1 h. After dilution with ethyl acetate, the solution was washed successively with saturated sodium hydrogen carbonate solution, 5% aqueous citric acid, water (×2) and brine, dried and then concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 50, 70 and 90% ethyl acetate in hexane to give the title compound as a yellow foam (1.138 g, 83%); νmax (CH2Cl2) 3389, 1783, 1732, 1682, 1516 cm-1 ; δH (CDCl3, 250 MHz) 1.53-1.70 (1H, m), 1.88-2.01 (2H, m), 2.28-2.41 (1H, m), 3.33 and 3.62 (2H, ABq, J 18.7 Hz), 3.79-3.98 (2H, m), 3.81 (3H, s), 4.08 (3H, s), 4.94 (1H, dd, J 9.0, 6.7 Hz), 5.04 (1H, d, J 4.8 Hz), 5.18 (2H, s), 5.88 (2H, br s, exch.), 5.98 (1H, dd, J 9.0, 4.8 Hz), 6.90 (2H, d, J 8.6 Hz), 6.94 (1H, s), 7.35 (2H, d, J 8.6 Hz), 7.50 (1H, br. d, J 9.0 Hz, exch.). [Mass spectrum: +ve ion (thioglycerol) MH+ (574)].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[S:13](Cl)([CH3:16])(=[O:15])=[O:14].N1C=CC=CC=1>C(Cl)Cl>[S:13]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)([CH3:16])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: CCOC(=O)Cc1csc(=N)[nH]1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NS(C)(=O)=O)n1

Procedure:
A mixture of ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (5.6 g.), mesyl chloride (6.9 g.), pyridine (15 ml.) and methylene chloride (45 ml.) was refluxed for 5 hours. After the reaction, the reaction mixture was concentrated. The residue was poured into ice-water (150 ml.) and stirred. The precipitates were collected by filtration, washed with water and diethyl ether and dried to give pale brown powder of ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (6.3 g.).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].N([O-])=[O:11].[Na+]>C(O)(=O)C.O>[O:11]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=O)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 50 g portion of ethyl acetoacetate in 60 ml of acetic acid was stirred at 0° C. to 10° C., as a solution of 30 g of sodium nitrite in 50 ml of water was added dropwise. When addition was complete, the mixture was stirred at 0° to 10° C. for 30 minutes and then diluted with 300 ml of ice water. The mixture was stirred for 2 hours and then extracted with 500 ml of dichloromethane. The dichloromethane layer was separated, washed with two 500 ml portions of ice water, dried, filtered and evaporated in vacuo. The residual oil was stirred vigorously with 200 ml of hexane and the resulting solid collected, washed with hexane and air dried, giving 31.4 g of 2,3-dioxobutyric acid, ethyl ester, (Z)-2-oxime.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[CH3:53][OH:54].[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:53][O:54][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:3]=1
Reactant: CO
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Agent: [F-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(OC)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
tert-Butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.12 g, 0.192 mmol), Cu(I)I (0.0365 g, 0.192 mmol), 1,10-phenanthroline (0.0346 g, 0.192 mmol), methanol (0.389 mL, 9.59 mmol) and KF on Al2O3 (40%; 0.195 g, 1.34 mmol) in toluene (4 mL) was stirred at 110° C. for 20 hours. The reaction was cooled to room temperature. Ethyl acetate (10 mL) was then added, and the reaction mixture was filtered through a pad of celite. The filtrate was concentrated to dryness. The resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give tert-butyl 4-(3-methoxy-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.098 g, 96%) as a solid. MS APCI (+) m/z 530.4 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.06 (s, 1H), 7.46 (m, 2H), 7.33 (m, 3H), 7.20 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.38 (s, 2H), 3.98 (s, 3H), 3.71 (s, 3H), 3.29 (m, 4H), 2.94 (m, 4H), 1.37 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].C(N(CC)CC)C.[C:32](Cl)(=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>ClCCl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32](=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)NCCOCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
Under a nitrogen atmosphere, a suspension of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (140.5 mg, 0.428 mmol) in a mixture of dichloromethane (3.5 mL) and triethylamine (150 μL, 1.07 mmol) was cooled to 0° C. Palmitoyl chloride (130 μL, 0.428 mmol) was slowly added. The reaction mixture was allowed to stir at 0° C. for 2 hours at which time analysis by thin layer chromatography indicated that there was no starting material left. The reaction mixture was diluted with dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (2×5 mL), dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (12 g of silica gel eluted with 2% methanol in dichloromethane) to provide 183 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)hexadecanamide as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[S:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.Br[CH2:24][CH2:25][CH2:26]Br>C(O)C>[CH2:24]([S:22][C:11]1[NH:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)[CH2:25][CH2:26][S:22][C:11]1[NH:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: BrCCCBr
Reactant: COc1ccc(-c2[nH]c(=S)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: CCO
Product: COc1ccc(-c2nc(SCCCSc3nc(-c4ccc(OC)cc4)c(-c4ccc(OC)cc4)[nH]3)[nH]c2-c2ccc(OC)cc2)cc1

Procedure:
A mixture of 4,5-bis(4-methoxyphenyl)-1H-imidazole-2-thione (15.6 g, 0.05 mol) and 1,3-dibromopropane (5 g, 0.025 mol) in ethanol (150 ml) was refluxed for three hours. After cooling, the resulting solid was removed by filtration and discarded. The solvent was removed at reduced pressure to give a yellow foam which was then treated with chloroform-ether. The resulting solid material was removed by filtration, dissolved in chloroform and washed with 10% aqueous sodium hydroxide solution. The solvent was removed at reduced pressure to give the title compound.
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N-:25]=[C:26]=[O:27]>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:26]([NH:25][CH:4]([CH2:5][CH3:6])[CH3:3])=[O:27])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: [N-]=C=O
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccc(Cl)cc1
Agent: Cl
Product: CCC(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]azetidine hydrochloride (98) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[CH3:9][S:10][CH2:11]Cl.C(N(CC)CC)C>>[CH3:1][C:2](=[CH:6][CH2:7][CH3:8])[C:3]([O:5][CH2:9][S:10][CH3:11])=[O:4]
Reactant: CSCCl
Reactant: CCC=C(C)C(=O)O
Solvent: CCN(CC)CC
Product: CCC=C(C)C(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting 2-methyl-2-pentenoic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 56°-57° C./2 mm Hg, n20 1.4861.