Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:2]([C:10]([O-:12])=O)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[Na+].[C:14]([C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[O:20][CH:21]1[CH2:24][NH:23][CH2:22]1)([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:14]([C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[O:20][CH:21]1[CH2:22][N:23]([C:10]([C:2]2[N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][N:4]3[CH:3]=2)=[O:12])[CH2:24]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C([O-])c1cn2ccccc2n1
Reactant: CC(C)(C)c1ccccc1OC1CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1OC1CN(C(=O)c2cn3ccccc3n2)C1
Yield: 97.2 %

Procedure:
To a stirred solution of sodium imidazo[1,2-a]pyridine-2-carboxylate (0.19 g, 1.0 mmol), 3-(2-tert-butylphenoxy)azetidine (0.21 g, 0.53 mmol) and DIPEA (0.39 g, 3.0 mmol) in DMF (5.0 mL) was added HBTU (0.76 g, 2.0 mmol) at room temperature. After 1 h the reaction mixture was diluted with ethyl acetate (50 mL) and washed with a 10% K2CO3 solution (3×20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, ethyl acetate to 95:5 methanol/ethyl acetate) to provide (3-(2-tert-butylphenoxy)azetidin-1-yl)(imidazo[1,2-a]pyridin-2-yl)methanone (0.18 g, 51%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][S:12]([CH3:15])(=[O:14])=[O:13])[C:8]([CH3:16])=[CH:7][C:6]=1[OH:17])(=O)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][S:12]([O:11][C:9]1[C:8]([CH3:16])=[CH:7][C:6]2[O:17][C:1]([CH3:2])=[N:4][C:5]=2[CH:10]=1)(=[O:13])=[O:14]
Reactant: CC(=O)Nc1cc(OS(C)(=O)=O)c(C)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1nc2cc(OS(C)(=O)=O)c(C)cc2o1

Procedure:
5.18 g of 2-acetylamino-4-methanesulfonyloxy-5-methylphenol and 0.8 g of p-toluenesulfonic acid were added to 100 ml of toluene and heated at reflux for 12 hours. After cooling and washing with water, concentration under a reduced pressure yielded crude crystals of 5-methanesulfonyloxy-2,6-dimethylbenzoxazole. Immediately the product was dissolved in 50 ml of methanol, to which 5 ml of water containing 2 g of sodium hydroxide was added. A crystalline product was obtained after 1 hour of reflux followed by neutralization with hydrochloric acid after cooling.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH:12]=[CH2:13])[CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([Li])[CH2:16][CH2:17]C.CN(C)P(N(C)C)(N(C)C)=O.ICCC>O1CCCC1>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH:12]=[CH2:13])[CH2:8][C:9]#[C:10][CH2:15][CH2:16][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: C#CCN(CC=C)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCI
Product: C=CCN(CC#CCCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
A solution of allyl-prop-2-ynyl-carbamic acid tert-butyl ester (prepared according to the method of Boger et al., J. Am. Chem. Soc., 1996, 118, 2109; 1.95 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at 0° C. and treated with n-butyllithium (1.6 M solution in hexane; 7.2 mL, 11.5 mmol) during a 5 min period. After being stirred for an additional 5 min, the solution was treated sequentially with hexamethylphosphoramide (2 mL) and a solution of 1-iodopropane (1.71 mL, 17.5 mmol) in tetrahydrofuran (2 mL). After 65 min, the cooling bath was removed and the mixture was allowed to warm to room temperature where it stirred for 80 min. At the conclusion of this period, saturated aqueous ammonium chloride was added, followed by water to dissolve the solids. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to yield a residue. The residue was purified by flash chromatography to provide a pale yellowish oil (1.67 g, 70%). 1H NMR (400 MHz, CDCl3) δ 5.80 (m, 1H), 5.17 (m, 2H), 4.1-3.9 (m, 4H), 2.17 (m, 2H), 1.60 (m, 2H), 1.48 (s, 9H), 0.99 (m, 3H). MS (ES+) m/z 238.27 (M+H+)
Reaction SMILES: O.[OH-].[Li+].[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[S:31][CH:32]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCCC1.CO>[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[S:31][CH:32]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2csc(-c3ccccc3)n2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2csc(-c3ccccc3)n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
Lithium hydroxide monohydrate (54.8 mg) was added to a solution of methyl E-4-phenyl-4-[4-(2-phenyl-4-thiazolylmethoxy)benzyloxyimino]butyrate (424 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.4 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain E-4-phenyl-4-[4-(2-phenyl-4-thiazolylmethoxy)benzyloxyimino]butyric acid (369 mg, yield 90%) as colorless crystals. m.p. 104-105° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[N:25][C:26]([Cl:32])=[CH:27][CH:28]=2)[N:23]=1>>[Cl:32][C:26]1[N:25]=[C:24]2[C:29]([CH:30]=[CH:31][C:22]([N:13]3[CH:12]([O:8][CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:21])=[N:23]2)=[CH:28][CH:27]=1
Reactant: CN1CCC(O)CC1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: [H-]
Agent: [Na+]
Product: CN1CCC(OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 19.7 %

Procedure:
Working in a manner similar to that described in Example 6, but starting with 1-methyl-4-piperidinol (4.3 g), sodium hydride (0.9 g) and 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (12.4 g), and heating the reaction mixture for 90 minutes under reflux, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(1-methyl-4-piperidyloxy)-1-isoindolinone (3 g), m.p. 204° C., is obtained after recrystallization in ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)C(O)Cc1ccc(Cl)cc1
Reaction time: 8 h
Yield: 64 %

Procedure:
Into 15.00 g β-(4-chlorophenyl)pyruvic acid, 98.00 g Zn(Hg), 219 mL of 2.5 mol·L1 hydrochloric acid and 35 mL THF solution were added, heated for refluxed for 10 h. After the filtration was performed when the reaction mixture was hot, the filtrate was concentrated to reach 80 mL and stood overnight. After sucking filtration, washing, drying and recrystallizing in boiling-water, a white floccular crystal was obtained in a yield of 64.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12][CH2:11][N:10]1[C:18]([O:20][CH3:21])=[O:19].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:34]([O:36][C:37](=[O:42])[CH2:38]C([O-])=O)[CH3:35].[K+].[Cl-].[Mg+2].[Cl-].Cl>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15](=[O:17])[CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:42])[CH2:12][CH2:11][N:10]1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)N1CCC(C(=O)O)CC1c1ccc(F)cc1Cl
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(c2ccc(F)cc2Cl)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
2-(2-Chloro-4-fluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.13 g, 6.75 mmol) (reference compound 21) was dissolved in methyl THF (50 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (1.641 g, 10.12 mmol) was added. The suspension was stirred at room temperature for 3 h (flask 1). In a separate flask was potassium 3-ethoxy-3-oxopropanoate (2.067 g, 12.14 mmol) suspended in methyl THF (25 mL) and magnesium chloride (1.156 g, 12.14 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 15 h using an oversized stirring bar. The contents of flask 1 was added to flask 2 and the resulting white suspension was stirred at room temperature for 20 h. In a separate flask was potassium 3-ethoxy-3-oxopropanoate (1.033 g, 6.07 mmol) suspended in methyl THF (25 mL) and magnesium chloride (0.578 g, 6.07 mmol) was added. The suspension was stirred at 50° C. for 15 h and then added to the reaction mixture. The mixture was stirred at room temperature for 15 h. 0.1 M HCl and DCM were added and the phases separated. The aqueous phase was extracted with DCM, the combined organic layers filtered through a phase separator and evaporated. The residue was purified via Biotage (gradient 2:1->1:1 heptane:EtOAc, Biotage® KP-SIL 340 g column, 10 CV). Methyl 2-(2-chloro-4-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.655 g, 63.6%) was isolated as a colorless oil. MS m/z 386 (M+H)+
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=O.[F:13][C:14]1[CH:25]=[CH:24][C:17]([CH2:18][C:19]2[CH2:23][CH2:22][CH2:21][N:20]=2)=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+].O>C(OCC)C.C(O)C>[F:13][C:14]1[CH:25]=[CH:24][C:17]([C:18]2[C:3]([C:5]3[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=3)=[CH:2][N:20]3[C:19]=2[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=1
Reactant: CSc1ccc(C(=O)CBr)cc1
Reactant: Fc1ccc(CC2=NCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CSc1ccc(-c2cn3c(c2-c2ccc(F)cc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.9 %

Procedure:
2-Bromo-1-(4-methylsulphanylphenyl)-1-ethanone (0.83 g, 3.4 mmol), dissolved in diethyl ether (10 ml), is treated with a solution of 2-(4-fluorobenzyl)-1-pyrroline (0.6 g, 3.3 mmol) in ethanol (10 ml) and NaHCO3 (0.6 g, 7 mmol). The mixture is stirred in the dark at RT for 18 h. The reaction is checked by TLC: SiO2/hexane-ether 9:1. The mixture is treated with H2O (10 ml), extracted 2 times with diethyl ether (100 ml) and the combined ether phase is then rewashed with water (30 ml). The organic phase dried over Na2SO4 Sicc. is concentrated in vacuo. The residue which remains is purified by CC on Al2O3/hexane/diethyl ether 1:1. Fractions 1-3 afford 330 mg of orange-red oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[CH:20]=[CH:19][N:18]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(N(CC)CC)C>[C:26]([O:24][CH2:23][C:22]1[C:17]([N:10]2[N:9]=[CH:8][C:7]3[C:12](=[C:13]([F:15])[CH:14]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)[C:11]2=[O:16])=[N:18][CH:19]=[CH:20][C:21]=1[Cl:25])(=[O:28])[CH3:27]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3CO)ncc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OCc1c(Cl)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 116a (1.6 g, 4.4 mmol), acetic anhydride (10 mL), and triethylamine (1 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 116b as a brown solid (1.4 g, 82%). MS: [M+H]+ 404.3.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 54.7 %

Procedure:
To a slurry of 212.0 g of 2,4-dinitrobenzoic acid in 1400 ml of toluene was added with agitation 101.0 g of triethylamine, followed by 122.7 g of N-methylpiperazine. Next 75.7 g of phosphorus oxychloride was added dropwise at such a rate to maintain the reaction temperature below 90° C. The mixture was refluxed for 5 hrs, cooled to 80° C., and poured slowly into 1000 ml of aqueous 5% NaHCO3 solution with stirring. The precipitate was filtered, washed with water and recrystallized from hot methanol to yield 161 g of N1 -methyl-N4 -(2,4-dinitrobenzoyl)piperazine, mp 130°-132° C.
Reaction SMILES: [C:1]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(O)C.[OH-].[Na+:26]>O>[C:1]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([O-:20])=[O:19])=[CH:13][CH:12]=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Na+:26]
Reactant: CC(C(=O)O)c1ccc(NC(=O)c2ccccc2O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)[O-])c1ccc(NC(=O)c2ccccc2O)cc1
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A solution of 53.05 g (0.186 mol) of 2-(4-(N-salicyloyl)aminophenyl)propionic acid and 300 ml of ethanol was treated with 7.59 g (0.190 mol) of NaOH dissolved in 22 ml of water. The reaction mixture was stirred for 30 min at 25C. and for 30 min at 0° C. The resulting pale yellow solid was isolated by filtration to give 52.61 g of sodium 2-(4-(N-salicyloyl)aminophenyl)propionate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31]([CH:32]4[CH2:34][CH2:33]4)=[N:30][N:29]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[N:19]=[C:18]3[N:29]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[N:30]=[C:31]([CH:32]4[CH2:33][CH2:34]4)[C:17]=23)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(C2CC2)nn3C2CCCCO2)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(-c3ccc(O)cc3)nc3c2c(C2CC2)nn3C2CCCCO2)CC1
Yield: 82.5 %

Procedure:
To a solution of 790 mg of 4-[3-cyclopropyl-6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester in 6 ml of dry THF 11.5 ml of borane-dimethylsulfide complex (1 M in DCM) was added slowly at r.t., and the reaction was heated to reflux for 0.5 h. The reaction was quenched by the addition of 7 ml of methanol, and the solvents were evaporated. The residue was purified by flash chromatography (silica, heptanes/ethyl acetate) yielding 635 mg (82%) of the title compound.
Reaction SMILES: C([NH:3][C:4]([NH:6][CH:7]1[CH2:9]C1)=[NH:5])#N.[ClH:10].N1CC[O:14][CH2:13][CH2:12]1>C(O)(C)C>[ClH:10].[N:6]1([C:4](=[NH:5])[NH2:3])[CH2:7][CH2:9][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: N#CNC(=N)NC1CC1
Agent: Cl
Solvent: CC(C)O
Product: N=C(N)N1CCOCC1
Temperature: 160 °C
Yield: 85 %

Procedure:
A mixture of 4.0 g (32.3 mmoles) of N-cyano-N'-cyclopropylguanidine and 3.98 g (32.3 mmoles) of morpholine hydrochloride is heated at 160° C. under a nitrogen atmosphere for 2 and a half hours. The solid mass obtained is dissolved in 200 ml of boiling isopropyl alcohol. The mixture is filtered hot and the filtrate is concentrated until a solid suspension appears. The mixture is then cooled to room temperature and 200 ml of diethyl ether are added. The reaction product crystallizes. It is filtered, washed with diethyl ether and dried. 6.8 g of N-]imino(cyclopropylamino)methyl]-4-morpholinecarboximidamide hydrochloride are obtained. Yield: 85%. M.P.: 195°-196° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]([CH:39]=O)[CH:30]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:39][C:31]3[CH:30]=[N:29][C:38]4[C:33]([CH:32]=3)=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cnc5ccccc5c4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and quinoline-3 carbaldehyde. MS (ESI) m/z 518.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH:18]=[CH:19][C:12]=2[NH:11][C:10](=[O:30])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH:18]=[CH:19][C:12]=2[N:11]([CH3:31])[C:10](=[O:30])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CN(Cc2ccccc2)C(=O)c2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)CN(Cc2ccccc2)C(=O)c2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
4-Benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (9.80 mg, 0.024 mmol) and K2CO3 (10 mg, 0.072 mmol, 3.0 equiv.) were placed in a 0.5-2 mL Smith process vial under a nitrogen atmosphere. To the vial were added DMF (0.5 mL) and iodomethane (2.25 μL, 0.036 mmol, d=2.28 g/cm3, 1.5 equiv) at room temperature. After heating, stirred, at 60° C. for 2 hours, the reaction mixture was concentrated en vacuo. The resulting crude mixture was diluted with acetonitrile (1 mL), filtered through a syringe filter and injected into a preparative HPLC to give desired product (4-benzyl-1-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione, 1.8 mg) as a yellow film.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][N:24]([O:28]C(=O)C)[C:25](=[O:27])[CH3:26])[CH:17]=3)[C:12]2=[O:32])=[CH:4][CH:3]=1.O.[OH-].[Li+]>C(O)(C)C.O.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][N:24]([OH:28])[C:25](=[O:27])[CH3:26])[CH:17]=3)[C:12]2=[O:32])=[CH:4][CH:3]=1
Reactant: CC(=O)ON(CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O)C(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)O
Solvent: O
Product: CC(=O)N(O)CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O

Procedure:
2-[3-(4-Fluorophenyl)-propyl]-6-[2-(N-acetyloxy-N-acetylamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline (2.0 g) is dissolved in 40 ml of an isopropanol/water mixture (1:1) and treated with 0.94 g (25 mmol) of lithium hydroxide monohydrate for 30 minutes at room temperature. The mixture is diluted with ether and the organic phase is removed. The aqueous layer is brought to pH of approximately 3 with 2N HCl, and extracted with ether. The combined acidic extracts are dried (MgSO4) and evaporated to dryness to yield 2-[3-(4-fluorophenyl)-propyl]-6-[2-(N-hydroxy-N-acetylamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: C(O)C=C.[Cl:5][CH2:6][C:7]([CH3:26])=[CH:8][CH2:9][CH2:10][C:11]([CH3:25])=[CH:12][CH2:13][CH2:14][C:15]([CH3:24])=[CH:16][CH:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][OH:20].[Mn]([O-])([O-])(=O)=O.[Ba+2]>C(Cl)Cl>[Cl:5][CH2:6][C:7]([CH3:26])=[CH:8][CH2:9][CH2:10][C:11]([CH3:25])=[CH:12][CH2:13][CH2:14][C:15]([CH3:24])=[CH:16][CH:17]=[C:18]([CH:21]([CH3:22])[CH3:23])[CH:19]=[O:20]
Reactant: CC(=CCCC(C)=CCCC(C)=CC=C(CO)C(C)C)CCl
Agent: O=[Mn](=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C=CCO
Solvent: ClCCl
Product: CC(=CCCC(C)=CCCC(C)=CC=C(C=O)C(C)C)CCl
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of the allylalcohol which is 14-chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraen-1-ol (492 mg, 1.51 mmol) in methylene chloride (22 ml) is added powdered barium manganate (8.5 g) and the mixture is vigorously stirred under argon atmosphere. After 8 hours, disappearance of the starting compound is confirmed and the reaction mixture is filtered and washed. The filtrate and the washing liquid are combined and concentrated. The resulting residue is purified by silica gel column chromatography (n-nexane/ethyl acetate =15:1) to give the desired 14-chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenal (468 mg, 95%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]1([CH2:36][O:37][C:38](=[O:49])[C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[C:41]([OH:48])[CH:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.CN(C)C=O>[C:30]1([CH2:36][O:37][C:38](=[O:49])[C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[C:41]([O:48][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:9]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])c(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)c1
Yield: 64.9 %

Procedure:
A mixture of 5.8 g (0.013 mol) of 1-(6-bromohexyl)-2,3-bis(phenylmethoxy)benzene, 3.5 g (0.013 mol) of 3-hydroxy-4-nitrobenzoic acid phenylmethyl ester, 3.5 g (0.026 mol) of anhydrous potassium carbonate and 2.9 g (0.019 mol) of sodium iodide in 125 ml of acetone and 13 ml of dimethylformamide was stirred and heated at reflux for 42 hours. Workup as described in example 16 and purification by HPLC using 10% ethyl acetate-hexane gave 5.45 g of 4-nitro-3-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid phenylmethyl ester as an oil.