Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]([CH3:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1.[CH3:17][NH:18][CH3:19].C(O)C>>[CH3:17][N:18]([CH2:2][C@@H:3]1[O:8][CH2:7][C@@H:6]([CH3:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1)[CH3:19]
Reactant: CNC
Reactant: C[C@@H]1CO[C@H](CCl)CN1Cc1ccccc1
Solvent: CCO
Product: C[C@@H]1CO[C@@H](CN(C)C)CN1Cc1ccccc1
Temperature: 150 °C

Procedure:
A mixture of (2S,5R)-2-(chloromethyl)-5-methyl-4-benzylmorpholine (1 equivalent) and dimethylamine in ethanol (33%, approx. 5.6 M, 5 equivalents) was heated at 150° C. over 2 days in a glass pressure vessel. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1 N HCl, and the solution was washed with CH2Cl2. The water phase was made basic with 30% NaOH solution (to pH=12) and extracted with CH2Cl2. The organic extracts were collected and dried (Na2SO4). Evaporation of the solvent under reduced pressure afforded (2S,5R)-2-[dimethylamino(methyl)]-5-methyl-4-benzylmorpholine as a brown oil which was used in the next step without purification. GC/MS: 247 (2%, M−H), 204 (55%, M−NMe2), Rt 15.5 minutes; LC/MS m/z 249.2 (MH+), Rt 0.72 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[C:28]([I:29])=[CH:27][NH:26][N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:36][Si:37]([CH3:44])([CH3:43])[CH2:38][CH2:39][O:40][CH2:41]Cl>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[C:28]([I:29])=[CH:27][N:26]([CH2:41][O:40][CH2:39][CH2:38][Si:37]([CH3:44])([CH3:43])[CH3:36])[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(-c2n[nH]cc2I)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(I)c(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a mixture of 3-(2,4-bis-benzyloxy-5-chloro-phenyl)-4-iodo-1H-pyrazole (4.46 g, 8.63 mmol) and caesium carbonate (8.43 g, 25.88 mmol) in DMF (50 ml) was added 2-(trimethylsilyl)ethoxymethyl chloride (2.29 ml, 12.94 mmol). The mixture was stirred at room temperature overnight before being partitioned between water and DCM. The organics were then washed with brine and water and concentrated in vacuo to give a yellow oil which was purified by column chromatography using hexanes and ethyl acetate as eluent, yielding 3-(2,4-bis-benzyloxy-5-chloro-phenyl)-4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole as a clear colourless oil (4.44 g, 80%).
Reaction SMILES: [CH2:1](O)[CH3:2].[C:4](OCC)(=O)C.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11].[OH-].[K+]>C(I)CC.CN(C)C=O.[N+](C1C=CC=CC=1)([O-])=O>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([N:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:4][CH2:1][CH3:2])=[CH:17][CH:18]=1)([O-:12])=[O:11].[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: CCO
Reactant: CCOC(C)=O
Agent: O=[N+]([O-])c1ccc(Nc2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCI
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CN(C)C=O
Product: CCCN(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1

Procedure:
0.90 g of 2,6-difluorobenzoylisocyanate was added to a solution of 1.27 g of 4-[N-(4-chlorophenyl)-N-propylamino]aniline in 15 ml of dry diethylether while stirring at room temperature. After 1.5 hours at room temperature the formed precipitate was sucked off, washed with acetonitrile and diethylether, and dried. The desired product was obtained in a yield of 1.50 g; melting-point 169°-169.5°C. The starting aniline was obtained from the corresponding nitro compound by reduction with hydrogen under the influence of Raney nickel as a catalyst; a mixture of equal parts by volume of ethanol and ethyl acetate was used as a solvent. 1-Nitro-4-[N-(4-chlorophenyl)-N-propylamino]benzene was prepared by an alkylation of 1-nitro-4-(4-chloroanilino) benzene with propyliodide in dimethylformamide as a solvent under the influence of KOH, 1-Nitro-4-(4-chloroanilino) benzene was formed by a coupling at high temperature of p-chlorobenzeneisocyanate and p-nitrophenyl in nitrobenzene as a solvent. In a corresponding manner, in which, if desired, instead of diethylether acetonitrile was used as a solvent for the urea-formation, the following compounds were prepared; the compound numbers correspond with the numbers given before in the specification:
Reaction SMILES: [BH3-][C:2]#[N:3].[Na+].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:22][C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH:31]3[CH2:37][CH2:36][CH2:35]N[CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[O:24])=[C:10]([CH:21]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1)=[O:12].C=O>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:22][C:23]([CH:25]2[CH2:26][CH2:27][N:28]([CH:31]3[CH2:37][CH2:36][CH2:35][N:3]([CH3:2])[CH2:33][CH2:32]3)[CH2:29][CH2:30]2)=[O:24])=[C:10]([CH:21]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1)=[O:12]
Reactant: [BH3-]C#N
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NC(=O)C1CCN(C2CCCNCC2)CC1
Agent: C=O
Agent: [Na+]
Product: CN1CCCC(N2CCC(C(=O)Nc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)CC2)CC1

Procedure:
Alternatively, 5-chloro-2-[1-(1-methyl-hexahydroazepin-4-yl)piperidin-4-ylcarbonylamino]-N-(5-chloropyridin-2-yl)-benzamide is prepared by a NaCNBH3 reductive alkylation of 5-chloro-2-[1-(hexahydroazepin-4-yl)piperidin-4-ylcarbonylamino]-N-(5-chloropyridin-2-yl)benzamide with formaldehyde.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=CC=CC=1.N[C@H:14](C(O)=O)C(C)C.N[C@H](C(O)=O)CC(C)C.N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1.N[C@H](C(O)=O)CCSC.NCC(O)=O.N[C@H](C(O)=O)CS.N[C@H](C(O)=O)CC1C=CC(O)=CC=1.N[C@H](C(O)=O)[C@@H](C)O.N[C@H](C(O)=O)CCC(=O)O.N[C@H](C(O)=O)CC(=O)N.N[C@H](C(O)=O)CCC(=O)N.N[C@H](C(O)=O)CC(=O)O.N[C@H](C(O)=O)CCCCN.N[C@H](C(O)=O)CCCNC(=N)N>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[C@H:3]([CH2:4][CH3:9])[CH3:14]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: C[C@@H](O)[C@H](N)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
Phe 0.61; Val 0.54; Leu 0.53; Trp 0.37; Met 0.26 Ala 0.25; Gly 0.16; Cys 0.04; Tyr 0.02; Pro -0.07; Thr -0.18; Ser -0.26; His -0.40; Glu -0.62; Asn -0.64; Gln -0.69; Asp -0.72; Lys -1.10; Arg -1.76.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl-].[F:9][C:10]1[C:15]([N:16]([CH3:36])[C:17]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])[C:20]=2[C:32]([F:35])([F:34])[F:33])=[O:18])=[CH:14][CH:13]=[C:12]([F:37])[C:11]=1[CH2:38][NH3+:39].N1C=CC=CC=1>C1COCC1>[C:1]([NH:39][CH2:38][C:11]1[C:10]([F:9])=[C:15]([N:16]([CH3:36])[C:17]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([F:31])([F:30])[C:26]([F:29])([F:27])[F:28])[C:20]=2[C:32]([F:33])([F:34])[F:35])=[O:18])[CH:14]=[CH:13][C:12]=1[F:37])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn1C)c1ccc(F)c(C[NH3+])c1F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)NCc1c(F)ccc(N(C)C(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)c1F
Reaction time: 20 h
Yield: 99.1 %

Procedure:
Acetic anhydride (34 mg, 0.34 mmol, 1.3 eq) in THF (1 ml) was added to a solution of [2,6-difluoro-3-(methyl{[1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)phenyl]methanaminium chloride (130 mg, 0.26 mmol) and pyridine (43 mg, 0.54 mmol, 2.1 eq.) in THF (2.5 ml), and the mixture was left at room temperature for 20 h. After concentration under reduced pressure, the product was purified by column chromatography (hexane/ethyl acetate) to give N-[3-(acetamidomethyl)-2,4-difluorophenyl]-N,1-dimethyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (131 mg, 99%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][S:13][C:14]2[NH:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[C:5]([CH3:23])=[CH:4][CH2:3]1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][S:13]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)=[O:32])[C:5]([CH3:23])=[CH:4][CH2:3]1
Reactant: CC1=CCN(C)c2c(CSc3nc4ccccc4[nH]3)cccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1=CCN(C)c2c(CS(=O)c3nc4ccccc4[nH]3)cccc21
Yield: 47.6 %

Procedure:
1,4-Dimethyl-8-(2-benzimidazolyl)thiomethyl-1,2-dihydroquinoline (0.4 g) was dissolved in dichloromethane (30 ml). To this solution was added dropwise a solution of m-chloroperbenzoic acid (0.27 g) in dichloromethane (5 ml) at -40° C. with stirring. After the mixture was stirred for 20 minutes at the same temperature, the reaction mixture was washed with an aqueous solution of sodium carbonate and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. Diethyl ether was added to the resulting residue to precipitate crystals. The resulting crystals were recrystallized from dichloromethane-diethyl ether to give 1,4-dimethyl-8-(2-benzimidazolyl)sulfinylmethyl-1,2-dihydroquinoline (0.2 g).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[OH-].[Mg+2:10].[OH-]>>[C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[Mg+2:10].[C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: CC(=O)CCC(=O)O
Agent: [Mg+2]
Agent: [OH-]
Product: CC(=O)CCC(=O)[O-]

Procedure:
In another experiment, the feasibility of the decomposition of the magnesium salt of levulinic acid was assessed using thermogravimetric analysis (TGA). Levulinic acid was neutralized using magnesium hydroxide to produce magnesium levulinate which was dried in an oven. Experiments were conducted using a TA Instruments Q500 TGA. Approximately 5 mg samples were loaded onto platinum pans as very thin layers.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.[Cl:17]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.CCCCCC>[Cl:17][C:8]1[CH:9]=[CH:10][N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CN(C)S(=O)(=O)n1cccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)n1ccc(Cl)n1
Temperature: -78 °C

Procedure:
To a solution of N-dimethylsulfamoylpyrazole (188.0 g, 1.07 mol) in dry tetrahydrofuran (1500 mL) at −78° C. was added dropwise a solution of 2.5 M n-butyl-lithium (472 mL, 1.18 mol) in hexane while maintaining the temperature below −65° C. Upon completion of the addition the reaction mixture was maintained at −78° C. for an additional 45 minutes, after which time a solution of hexachloroethane (279 g, 1.18 mol) in tetrahydrofuran (120 mL) was added dropwise. The reaction mixture was maintained for an hour at −78° C., warmed to −20° C. and then quenched with water (1 L). The reaction mixture was extracted with methylene chloride (4×500 mL); the organic extracts were dried over magnesium sulfate and concentrated. The crude product was further purified by chromatography on silica gel using methylene chloride as eluent to afford the title product compound as a yellow oil (160 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][CH2:9][CH:10]([C:14]([F:17])([F:16])[F:15])[C:11]([OH:13])=O)=[CH:5][CH:4]=1.[C:20]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)([CH3:23])([CH3:22])[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:20]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:11](=[O:13])[CH:10]([C:14]([F:17])([F:16])[F:15])[CH2:9][S:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: COc1ccc(CSCC(C(=O)O)C(F)(F)F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(CSCC(C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)C(F)(F)F)cc1

Procedure:
A solution of 3-(4-methoxybenzyl)thio-2-trifluoromethylpropanoic acid (6.5 g.) and proline tert-butyl ester (3.76 g.) in dichloromethane (500 ml.) is stirred at 0° and treated with dicyclohexylcarbodiimide (4.53 g.) After 30 minutes at 0° and overnight at room temperature, the mixture is filtered and the filtrate is washed neutral. The organic layer is dried and concentrated to dryness in vacuo. The TLC [silica gel methylene chloride/ethyl acetate (95:5)] shows two major spots Rf 0.46 and 0.51 corresponding to the two diastereoisomers.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:7][N:8]2[CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34]Cl>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:34][CH2:33][O:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:25]([OH:36])=[O:24])[CH2:19][CH2:18]3)=[CH:7][N:8]2[CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)cn(Cc3ccsc3)c2c1
Reactant: COC(=O)c1ccccc1OCCCl
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(Cc3ccsc3)c3cc(F)ccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.98 g (0.31 mmol) of 6-fluoro-3-piperidin-4-yl-1-thiophen-3-ylmethyl-1H-indole (example 108, part B) and 0.09 g (0.40 mmol) 2-(2-chloro-ethoxy)-benzoic acid methyl ester. The crude mixture was purified by HPLC-MS using a C-18 column.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:25][CH2:24]2)=[O:22])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Product: CC(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2cccc(Cl)c2)CC1
Yield: 47 %

Procedure:
The title compound was synthesized in analogy to example 5, from 1-{4-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carbonyl]-piperazin-1-yl}-2-methyl-propan-1-one (example 31) and 3-chlorophenylboronic acid to afford the desired product as a light-brown foam (47%). MS (ISP): 564.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([O:46][Si](C(C)(C)C)(C)C)[CH2:21][NH:22][C:23]([CH3:45])([CH3:44])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][C:34]34[CH2:43][CH:38]5[CH2:39][CH:40]([CH2:42][CH:36]([CH2:37]5)[CH2:35]3)[CH2:41]4)[CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:46])[CH2:21][NH:22][C:23]([CH3:44])([CH3:45])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][C:34]34[CH2:43][CH:38]5[CH2:37][CH:36]([CH2:42][CH:40]([CH2:39]5)[CH2:41]3)[CH2:35]4)[CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)NCC(O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)NCC(O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a solution of Intermediate 88 (0.748 g, 1.02 mmol) in tetrahydrofuran (15 mL) were added 0.546 g (1.73 mmol) of tetrabutylammonium fluoride. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude was partitioned between ethyl acetate and water. The organic layer was washed several times with water and the solvent was removed under reduced pressure. The crude was purified by column chromatography with silica gel, eluting with dichloromethane/methanol 90:4 to give 0.505 g (80% yield) of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:9]=[C:10](/[C:15](/[CH3:25])=[CH:16]\[CH:17]=[CH:18]\[C:19](\[CH3:24])=[CH:20]\[C:21]([OH:23])=O)[CH:11]=[C:12]([Br:14])[CH:13]=1.C[Si](C)(C)[O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][Si](C)(C)C)=[CH:31][CH:30]=1.[F-].[K+]>CN(C=O)C.CCOCC>[OH:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:21](=[O:23])/[CH:20]=[C:19](\[CH3:24])/[CH:18]=[CH:17]/[CH:16]=[C:15](\[C:10]2[CH:11]=[C:12]([Br:14])[CH:13]=[C:8]([Br:7])[CH:9]=2)/[CH3:25])=[CH:31][CH:30]=1
Reactant: C/C(=C/C=C/C(C)=C/C(=O)O)c1cc(Br)cc(Br)c1
Reactant: C[Si](C)(C)Nc1ccc(O[Si](C)(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C/C(=C/C=C/C(C)=C/C(=O)Nc1ccc(O)cc1)c1cc(Br)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of dry ether (30 mL) and DMF (0.5 g, 7 mmol) was cooled to 15° C. and then treated with oxalyl chloride (0.2 g, 1.5 mmol) and stirred for 15 min. All solvent was then removed and dimethylchloroformamidinium chloride (Helv. Chim. Acta 42, 1653 (1959)) as a white solid was suspended in DMF (5 mL). To this was added (2E,4E,6Z)-7-(3,5-dibromophenyl)-3,7-dimethyl-2,4,6-heptatrienoic acid (0.30 g, 0.8 mmol) and the mixture was stirred at room temperature for 3-4 h. The reaction was cooled to 0° C. and treated over a 10 min period with a solution of O,N-bis(trimethylsilyl)-4-aminophenol (0.6 g, 2.4 mmol) in DMF (5 mL). Once the addition was complete stirring was continued for 1 h and then it was poured into 5% aqueous KF (10 mL) and stirred a further 1 h. The aqueous mixture was extracted with ether, purified by HPLC using 35% EtOAc/hexanes as eluent to give N-(4-hydroxyphenyl)-(2E,4E,6Z)-7-(3,5-dibromophenyl)-3,7-dimethyl-2,4,6-heptatrienamide.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[C:23]([O:29]C)[C:22]=2[CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39]C)[CH:34]=2)=O)=[CH:4][CH:3]=1.[PH2](O)=O>Br>[OH:39][C:35]1[CH:34]=[C:33]([CH2:32][CH2:31][C:22]2[C:21]([CH2:20][CH2:19][NH:18][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=3)=[CH:26][CH:25]=[C:24]([OH:27])[C:23]=2[OH:29])[CH:38]=[CH:37][CH:36]=1
Reactant: COc1cccc(CCc2c(CCNC(=O)CCCCC(=O)NCCc3ccc(N)cc3)ccc(OC)c2OC)c1
Agent: Br
Agent: O=[PH2]O
Product: Oc1cccc(CCc2c(CCNCCCCCCNCCc3ccccc3)ccc(O)c2O)c1

Procedure:
A solution of the diamine Intermediate 10 (a) (1.4 g) in 48% aqueous hydrobromic acid (20 ml) containing hypophosphorous acid (0.1 ml) was heated at reflux temperature for 3 hours under an atmosphere of nitrogen. The solution was evaporated to dryness and the residue treated with ethyl acetate. The dihydrobromide salt of the title compound (1.3 g) was filtered off as a beige solid and dried at 80° under vacuum, mp 167°-170°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16].O=P(Cl)(Cl)[Cl:19].CCN(C(C)C)C(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:19])[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2c(Br)cccc2c(=O)n1C1CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c2cccc(Br)c2nc(Cl)n1C1CC1
Yield: 85.2 %

Procedure:
A mixture of 8-bromo-3-cyclopropylquinazoline-2,4(1H,3H)-dione (723b; 5.00 g, 17.79 mmol), POCl3 (8.29 mL, 89.0 mmol) and DIPEA (12.38 mL, 71.1 mmol) was stirred at reflux overnight. The reaction was then cooled and concentrated. The brown syrup was cooled in an ice bath and then ice was added to the reaction mixture. The brown sludge was added to 100 mL of 10 M NaOH (aq.) and ice and stirred for 20 min. The mixture was filtered and the brown solid was washed with water and then put into solution with CH2Cl2 and filtered. The filtrate was collected and dried over Na2SO4, filtered and concentrated to afford 8-bromo-2-chloro-3-cyclopropylquinazolin-4(3H)-one (723) (4.54 g, 15.16 mmol, 85% yield) as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.17 (dd, J=8.02, 1.56 Hz, 1H), 7.99 (dd, J=7.82, 1.56 Hz, 1H), 7.32 (t, J=7.92 Hz, 1H), 3.02 (tt, J=7.12, 4.03 Hz, 1H), 1.33-1.43 (m, 2H), 0.94-1.04 (m, 2H). m/z (ES, +ve) 298.9, 301.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])=[O:6]
Reactant: CCCCCCCCCCCCBr
Reactant: Nc1cc(C(=O)O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCOC(=O)c1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
17.2 g (0.1 mol) of 3-amino-4-chlorobenzoic acid was added to 50 ml of N,N-dimethylformamide. Then 13.8 g (0.1 mol) of potassium carbonate was added to the solution obtained above, and the resulting mixture was stirred in the temperature range of from 20 to 30° C. for 30 min. 27.4 g (0.11 mol) of dodecyl bromide was poured into the solution thus obtained, and the resulting solution was heated to 80° C., and allowed to react at the temperature for 1 hour. After completing the reaction, 50 ml of ethyl acetate, and 50 ml of water were added to the reaction mixture, and the organic layer was separated, concentrated, diluted with 100 ml of methanol, and then cooled to precipitate crystals. The crystals were separated by filtration, and then dried to obtain 32.3 g (yield 95%) of the desired product. Purity 99% or higher. Melting point 58.3-59.5° C. A result of the elemental analysis of this sample is as follows:
Reaction SMILES: [CH3:1][C:2]1O[C:5]([CH3:7])=[N:4][C:3]=1[CH3:8].[NH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:19]=[O:20])[CH2:15][CH2:14]1>C(O)(=O)C>[CH3:7][C:5]1[N:9]([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([CH:19]=[O:20])[CH2:17][CH2:18]2)[C:2]([CH3:1])=[C:3]([CH3:8])[N:4]=1
Reactant: Cc1nc(C)c(C)o1
Reactant: NCCCC1CCN(C=O)CC1
Solvent: CC(=O)O
Product: Cc1nc(C)n(CCCC2CCN(C=O)CC2)c1C
Temperature: 145 °C
Yield: 50 %

Procedure:
A mixture of trimethyloxazole (10.18 g, 0.091 M), 4[3-aminopropyl]-1-piperidinecarboxaldehyde and acetic acid (0.16 g) were heated at 145° C. for 6 hrs. After the reaction, the excess of trimethyl oxazole was removed at reduced pressure and the residue was purified on silica gel column eluted with 4 to 10% of methanol by volume in CHCl3 to yield 4-[3-(2,4,5,-trimethyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde as an oil (3.3 g, 50% yield).
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:11][OH:12].N1C=CC=CC=1>C(O)C>[C:1]1(=[N:11][OH:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCCCC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1CCCCCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution containing cyclooctanone (12.6 g, 0.1 mol) and hydroxylamine hydrochloride (14.0 g, 0.2 mole) in a mixture of pyridine (40 mL, 0.5 mole) and ethanol (50 mL) was stirred at ambient temperature for about 15 hours. The solvent was then removed by rotary evaporation. The residue was dissolved in diethyl ether (300 mL) then washed with hydrochloric acid (2×100 mL). The aqueous layer was extracted with diethyl ether (2×150 mL). The ether extracts were combined, dried over magnesium sulfate then concentrated to provide cyclooctanone oxime as a white solid.