Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH2:13])=[O:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[OH:20][C:21]([CH3:54])([CH3:53])[CH2:22][C@:23]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:28][CH2:27][N:26]([C@H:29]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH3:30])[C:25](=[O:46])[NH:24]1.O>C(O)C.C1(C)C=CC=CC=1.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>[OH:20][C:21]([CH3:53])([CH3:54])[CH2:22][C@:23]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:28][CH2:27][N:26]([C@H:29]([C:31]2[CH:32]=[CH:33][C:34]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4([C:11]([NH2:13])=[O:12])[CH2:10][CH2:9]4)=[N:6][CH:7]=3)=[CH:35][CH:36]=2)[CH3:30])[C:25](=[O:46])[NH:24]1
Reactant: NC(=O)C1(c2ccc(Br)cn2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
1-(5-Bromo-pyridin-2-yl)-cyclopropanecarboxylic acid amide (120 mg), Na2CO3 (443 mg), and Pd(PPh3)4 (12 mg) were added to a solution of (S)-4-(2-hydroxy-2-methylpropyl)-4-phenyl-1-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}tetrahydro-pyrimidin-2(1H)-one (200 mg; for preparation see WO 2009061498) in ethanol (6 mL), toluene (8 mL), and H2O (4 mL) at room temperature. The resulting mixture was stirred at 100° C. for 2 h under N2 atmosphere. After cooling to room temperature, the mixture was concentrated, diluted with H2O (30 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were concentrated to afford an oil which was purified by preparative HPLC to give the title compound. Yield: 124 mg (58% of theory); LC (method 4): tR=0.98 min; Mass spectrum (ESI+): m/z=513 [M+H]+; 1H NMR (CDCl3, 400 MHz) δ 0.69 (s, 3H), 1.29 (m, 2H), 1.31 (m, 3H), 1.50 (d, 3H), 1.79 (m, 2H), 1.98-2.07 (m, 3H), 2.12-2.22 (m, 3H), 2.70-2.83 (m, 1H), 4.55 (s, 1H), 5.80-5.62 (m, 2H), 7.21 (m, 3H), 7.28 (m, 1H), 7.33 (m, 4H), 7.70 (m, 2H), 7.78 (m, 1H) 8.69 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH:8]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[CH2:7][C:6]=2[NH:5][C:4](=[O:18])[CH:3]=1.[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH3:21][N:5]1[C:6]2[CH2:7][CH:8]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[CH2:9][C:10](=[O:12])[C:11]=2[C:2]([CH3:1])=[CH:3][C:4]1=[O:18]
Reactant: CI
Reactant: Cc1cc(=O)[nH]c2c1C(=O)CC(c1ccsc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(C)c2c1C(=O)CC(c1ccsc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-methyl-7-(thiophen-3-yl)-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.518 g) in dimethylformamide (5 ml) was added at room temperature 60% sodium hydride (0.08 g) and then was added methyl iodide (0.3 ml), and the mixture was stirred at room temperature for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The resulting crystals were washed with ethyl acetate to give 1,4-dimethyl-7-(thiophen-3-yl)-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.405 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([O:21]CC)=O)=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:24][NH2:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([NH:25][CH3:24])=[O:21])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)COC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Reactant: CN
Product: CNC(=O)COC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.9 g (7.5 mmol) of 2-(ethyloxy)-2-oxoethyl 4-[(4-bromophenyl)oxy]-1-piperidinecarboxylate, prepared in Step 4.3, in solution in 10 ml of a 33% ethanolic solution of methylamine are stirred at ambient temperature for 20 hours. Following evaporation, the product is purified by chromatography on silica gel, eluting with ethyl acetate, to give 0.8 g of product in gum form, which is used as it is in the following step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:14]2[C:19]=1[C:18](=[O:26])[CH2:17][CH2:16][CH2:15]2
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc([N+](=O)[O-])c2c1CCCC2=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCOc1ccc(N)c2c1CCCC2=O
Reaction time: 1.5 h
Yield: 109.3 %

Procedure:
5-[3′-(t-Butoxycarbonylamino)propyloxy]-8-nitro-1,2,3,4-tetrahydronaphthalen-1-one (3.55 g) is dissolved in ethanol (160 ml), and thereto is added 10% palladium-carbon (420 mg). The mixture is stirred under hydrogen atmosphere for 1.5 hour, and the catalyst is removed by filtration. The filtrate is concentrated, and the residue is purified by silica gel column chromatography to give the title compound (3.56 g) as a yellow oil.
Reaction SMILES: Br.[CH3:2][O:3][C:4]([C:6]1[CH2:7][NH:8][CH2:9][CH2:10][CH:11]=1)=[O:5].C(N(C(C)C)C(C)C)C.[CH3:21][C:22]1([CH3:45])[CH:31]([CH2:32][CH2:33]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:23]1>CN(C)C=O>[CH3:2][O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:33][CH2:32][CH:31]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:23][C:22]2([CH3:21])[CH3:45])[CH2:9][CH2:10][CH:11]=1)=[O:5]
Reactant: COC(=O)C1=CCCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2Cc3ccccc3OC2(C)C)cc1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1=CCCN(CCC2Cc3ccccc3OC2(C)C)C1
Reaction time: 15 h
Yield: 67 %

Procedure:
First 5.55 g (25 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide (guvacoline hydrobromide) and then 11.31 g (87.5 mmol) of N-ethyl-N,N-diisopropyl-amine are added to a solution of 9 g (25 mmol) of 2,2-dimethyl-3-[2-(4-toluenesulfonyloxy)-ethyl]-chroman in 100 ml of N,N-dimethylformamide. The solution is stirred for 15 hours at 60° and then concentrated by evaporation under a high vacuum. Water is added to the residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline with sodium hydroxide solution (30%) while cooling and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and concentrated by evaporation in vacuo, yielding 5.52 g (67% of theoretical yield) of 1-[2-(2,2-dimethylchroman-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester in the form of a light-yellow oil. 1-[2-(2,2 -dimethylchroman-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride, prepared therefrom with hydrochloric acid in diethyl ether, crystallises from methanol/diethyl ether and melts at 196°-197°.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:14]>[Pd].CO>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:15])([CH3:1])[C:3](=[O:14])[NH:4]2)=[CH:9][CH:8]=1
Reactant: CC1(C)C(=O)Nc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)C(=O)Nc2cc(N)ccc21
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A mixture of 3,3-dimethyl-6-nitroindolin-2-one (500 mg, 2.4 mmol), 10% Pd—C (100 mg), and MeOH (100 mL) was stirred under H2 (1 atm) for 3 h. After that the catalyst was filtered off and the filtrate was concentrated to give an off-white solid (420 mg).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]([O:12][CH3:13])[O:10][CH3:11])=[C:4]([CH3:14])[N:3]=1.C([Li])CCC.CN(C)[CH:22]=[O:23].O>O1CCCC1>[CH3:11][O:10][CH:9]([O:12][CH3:13])[C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH:22]=[O:23])=[N:3][C:4]=1[CH3:14]
Reactant: COC(OC)c1cc(C)c(Br)nc1C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(OC)c1cc(C)c(C=O)nc1C
Reaction time: 0.67 h
Yield: 35.4 %

Procedure:
To a solution of 2-bromo-5-dimethoxymethyl-3,6-dimethylpyridine (382 mg, 1.47 mmol) in tetrahydrofuran (6 mL) were added n-butyllithium (1.6 mol/L; 1,4 mL, 2.2 mmol) and dimethylformamide (0.23 mL, 3.0 mmol) sequentially at −78° C. under nitrogen atmosphere, and the mixture was stirred for 40 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (6:1 hexane/ethyl acetate) to afford 5-dimethoxymetyl-3,6-dimethyl-2-pyridinecarboxaldehyde (109 mg, 35%).
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=O)CCC.Cl.C(N=C=NCCCN(C)C)C.ON1C(=O)CCC1=O.C(Cl)(Cl)Cl.CO.[H][H].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>C(Cl)(Cl)Cl>[NH2:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:16])[NH2:17]
Reactant: [H][H]
Reactant: CCCCOC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N=C(N)NCCC[C@H](N)C(=O)O
Reaction time: 3 h

Procedure:
75 mg (0.101 mmol) of dioleoylphosphatidylethanolamine (Avanti Polar Lipids, USA) (DOPE), 34.3 mg (0.110 mmol) of Nalpha -tret-butoxycarbonyl-arginine hydrochloride (Sigma, USA), 24.8 mg (0.129 mmol) of N-ethyl-N'-dimethylaminopropyl-carbodiimide hydrochloride (Sigma, USA), and 14.9 mg (0.129 mmol) of N-hydroxysuccinimide (Sigma, UAS) were dissolved in 2 ml of chloroform and incubated with agitation at 37° C. for 3 hours. At that point, TLC (CHCl3 --CH3OH--H2 65:25:4, silica) showed 100% conversion of DOPE (Rf 0.49) into faster moving, ninhydrin-negative product (Rf 0.69), identified as N-(Nalpha -tret-butoxycarbonyl-arginyl)-DOPE. This product was purified by chromatography on silica and deprotected by treatment with 4M HCl in anhydrous dioxane for 3 hours. After removal of volatiles in vacuum, the residue was chromatographed on silica, eluent CHCl3 --CH3OH 7:3, to obtain Arg-PE (Rf 0.26 in the above system) with the yield of 10.8 mg (12% of theory). Phosphate to primary amino group ratio: Theory 1.0, Found 0.90±0.12.
Reaction SMILES: [ClH:1].CS(SCCN)=[C:4]([OH:6])[OH:5].C(N[C@@:15]1(O)[C@@H:21]([O:22]C(=O)C)[C@H:20](OC(=O)C)[C@@H:19]([CH2:30]OC(=O)C)[O:18][C@H]1S)(=O)C>CO>[ClH:1].[CH3:30][C:19]([CH2:20][C:21]([CH2:15][C:4]([OH:5])=[O:6])=[O:22])=[O:18]
Reactant: CC(=O)N[C@]1(O)[C@H](S)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CS(SCCN)=C(O)O
Agent: Cl
Solvent: CO
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 25 °C

Procedure:
HCl was prepared as follows. To a stirred solution of methyl-2-aminoethylsulfenylthiocarbonate HCl (447 mg, 2.196 mmol) in methanol (5 ml) was added 2-acetamido-3,4,6-tri-O-acetyl-1-thio-β-D-glucose (798 mg, 2.196 mmol) in methanol (10 ml). After stirring at room temperature over night, the mixture was evaporated to dryness yielding the triacetate as a white solid.
Reaction SMILES: C(O[C:6]([NH:8][CH:9]=[CH:10][C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:7])CCC.[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(O)(C)C>[CH2:14]([O:15][C:9]([N:8]=[C:6]=[O:7])=[CH:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:25][CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)[CH2:13][CH2:12][CH3:11]
Reactant: CCCCOC(=O)NC=Cc1ccc(OCC2CO2)cc1
Reactant: CC(C)N
Solvent: CC(C)O
Product: CCCCOC(=Cc1ccc(OCC(O)CNC(C)C)cc1)N=C=O

Procedure:
Analogously to the description in Example 2, 3.93 g (0.0135 mol) of 1-[p-(2-n-butoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane, on reaction with 1.22 ml (0.0142 mol) of isopropylamine in 50 ml of isopropanol, yield 1-[p-(2-n-butoxy-carbonylaminovinyl)-phenoxy]-2-hydroxy-3-isopropylaminopropane of melting point 125°-126°C (from acetone-ether).
Reaction SMILES: C1(N2CC3C(=O)N4N=C(C5C=CC(Cl)=CC=5)C=C4N(CC4C=CC=CC=4)C=3C2=O)CCCCC1.[CH:35]1([N:41]2[CH2:49][C:48]3[C:47](=[O:50])[N:46]4[N:51]=[C:52]([C:54]5[CH:59]=[CH:58][C:57](Cl)=[CH:56][CH:55]=5)[CH:53]=[C:45]4[N:44]([CH2:61][C:62](=[O:69])[C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[C:43]=3[C:42]2=[O:70])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(N1CC2C(=O)N3N=C(C4C=CC=CC=4)C=C3N(CC3C=CC=CC=3)C=2C1=O)CCCCC.C(N1CC2C(=O)N3N=C(C4C=CC=CC=4)C=C3N(CC(=O)C3C=CC=CC=3)C=2C1=O)CCCCC.C(N1CC2C(=O)N3N=C(C4C=CC(Cl)=CC=4)C=C3N(CC3C=CC=CC=3)C=2C1=O)CCCCC.C(N1CC2C(=O)N3N=C(C4C=CC(Cl)=CC=4)C=C3N(CC(=O)C3C=CC=CC=3)C=2C1=O)CCCCC>>[CH:35]1([N:41]2[CH2:49][C:48]3[C:47](=[O:50])[N:46]4[N:51]=[C:52]([C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)[CH:53]=[C:45]4[N:44]([CH2:61][C:62](=[O:69])[C:63]4[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=4)[C:43]=3[C:42]2=[O:70])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: O=C(Cn1c2c(c(=O)n3nc(-c4ccc(Cl)cc4)cc13)CN(C1CCCCC1)C2=O)c1ccccc1
Agent: CCCCCCN1Cc2c(n(CC(=O)c3ccccc3)c3cc(-c4ccc(Cl)cc4)nn3c2=O)C1=O
Agent: CCCCCCN1Cc2c(n(CC(=O)c3ccccc3)c3cc(-c4ccccc4)nn3c2=O)C1=O
Agent: CCCCCCN1Cc2c(n(Cc3ccccc3)c3cc(-c4ccc(Cl)cc4)nn3c2=O)C1=O
Product: O=C(Cn1c2c(c(=O)n3nc(-c4ccccc4)cc13)CN(C1CCCCC1)C2=O)c1ccccc1

Procedure:
6-Cyclohexyl-6,7-dihydro-4-(phenylmethyl)-2-(4-chlorophenyl)-4H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8-dione; 6-Cyclohexyl-6,7-dihydro-4-(2-oxo-2-phenylethyl)-2-(4-chlorophenyl)-4H-pyrazolo[1,5-a]pyrrolo[3,4-d]-pyrimidine-5,8-dione; 6-Hexyl-6,7-dihydro-4-(phenylmethyl)-2-phenyl-4H- pyrazolo[1,5-a]pyrrolo[3,4-d]-pyrimidine-5,8-dione; 6-Hexyl-6,7-dihydro-4-(2-oxo-2-phenylethyl)-2-phenyl-4H-pyrazolo [1,5-a]-pyrrolo [3,4-d]-pyrimidine-5,8-dione; 6-Hexyl-6,7-dihydro-4-(phenylmethyl)-2-(4-chlorophenyl)-4H-pyrazolo[1,5-a]pyrrolo[3,4-d]-pyrimidine-5,8-dione; 6-Hexyl-6,7-dihydro-4-(2-oxo-2-phenylethyl)-2-(4-chlorophenyl)-4H-pyrazolo[1,5-a]pyrrolo[3,4-d]-pyrimidine-5,8-dione are set forth in Table 15.
Reaction SMILES: Cl[CH:2]([OH:5])[CH2:3][CH3:4].[N+:6]([C:9]1([N+:13]([O-:15])=[O:14])[CH2:12][NH:11][CH2:10]1)([O-:8])=[O:7].[OH-].[Na+]>>[CH2:4]([N:11]1[CH2:12][C:9]([N+:13]([O-:15])=[O:14])([N+:6]([O-:8])=[O:7])[CH2:10]1)[CH:3]1[O:5][CH2:2]1
Reactant: O=[N+]([O-])C1([N+](=O)[O-])CNC1
Reactant: CCC(O)Cl
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])C1([N+](=O)[O-])CN(CC2CO2)C1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
In step (2), 1-chloropropanol-3,3-dinitroazetidine of Formula IV prepared in step (1) is cooled, and NaOH aqueous solution is slowly dropped. Thus obtained brown solution is warmed to room temperature and stirred for 3-10 hours. The solution obtained is washed with distilled water and then distilled with diethylether. Thus obtained organic layer is dried on K2CO3. The solvent is removed under lowered pressure and 1-glycidyl-3,3-dinitroazetidine is obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>C(#N)C>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][N:13]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](c4ccccc4)CC3)n1-2
Reactant: BrCc1ccccn1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Clc1ccc2c(c1)CN(Cc1ccccn1)Cc1nnc([C@H]3CC[C@H](c4ccccc4)CC3)n1-2
Temperature: 50 °C
Reaction time: 65 h

Procedure:
To a mixture of trans-8-chloro-1-(4-phenyl-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.065 g, 0.16 mmol) and potassium carbonate (0.073 ml, 0.53 mmol) in acetonitrile (1 ml) was added 2-(bromomethyl)pyridine hydrobromide (0.042 g, 0.16 mmol) at room temperature. Stirring for 65 h at 50° C. was followed by partitioning between 1 M aqueous sodium hydroxide solution (50 ml) and dichloromethane (50 ml). The layers were separated. The aqueous layer was extracted with one 50-ml portion of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.058 g, 79%) as white solid. MS m/e: 471 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.O[N:14]1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([NH2:14])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cccc(Br)c1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: NC(=O)CCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-(3-bromophenyl)propionic acid (93) (5.0 g, 21.8 mmol) and N-hydroxysuccinimide (2.51 gr., 21.8 mmole) in CH2Cl2 (100 ml) was added dicyclohexylcarbodiimide (4.50 g, 21.8 mmol) and the mixture was stirred at room temperature for 45 min. The precipitate was removed by filtration and the filtrate was cooled in an ice bath. Ammonia gas was bubbled into the solution for 2 min then allowed to warm to room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc. This solution was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure to an oil which was triturated with hexanes. The product was collected by filtration to give 3-(3-bromophenyl)propionamide (94) as a white solid. This material was taken on to the next synthetic step without further purification. Yield (4.62 g, 93%): 1H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H), 7.35 (dt, J=6.4, 2.4 Hz, 1H), 7.26 (br s, 1H), 7.18-7.24 (m, 2H), 6.75 (br s, 1H), 2.78 (t, J=7.6 Hz, 2H), 2.34 (t, J=7.6 Hz, 2H).
Reaction SMILES: N1C=CC=CC=1CC(=O)C.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:25]1[CH:26]=[C:27]([C@@H:31]([NH2:33])[CH3:32])[CH:28]=[CH:29][CH:30]=1>CS(C)=O>[O:17]([C:25]1[CH:26]=[C:27]([C@@H:31]([NH2:33])[CH3:32])[CH:28]=[CH:29][CH:30]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: C[C@H](N)c1cccc(Br)c1
Agent: CC(=O)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: C[C@H](N)c1cccc(Oc2ccccc2)c1
Temperature: 90 °C
Yield: 50.5 %

Procedure:
Into a 20 ml microwave vial was weighted 1-(pyridin-2-yl)propan-2-one ligand (90 mg, 0.665 mmol), phenol (407 mg, 4.32 mmol), CuBr (47.7 mg, 0.332 mmol) and Cs2CO3 (2166 mg, 6.65 mmol). To the mixture was added DMSO (5 ml) and (S)-1-(3-bromophenyl)ethanamine (0.5 ml, 3.32 mmol). The tube was flushed with N2, capped, and the black mixture heated in the oil bath at 90° C. for 18 hours. The heterogenous mixture was diluted with EtOAc and filtered through a glass-fritted funnel, eluting with EtOAc and another 5 mls of DMSO. The volatiles were then removed in vacuo and the crude brown liquid was filtered through 1 μm PTFE filter and purified by reverse phase HPLC. The combined product fractions were desalted by addition of equal amount of EtOAc and about 250 mg Na2CO3 in a separatory funnel. The phases were separated and the organic washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield (S)-1-(3-phenoxyphenyl)ethanamine (361.5 mg, 1.678 mmol, 50.5% yield) as an amber oil. LCMS m/z 214.1 (M+H)+, Rt 0.61 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH:8]2[C:13](=O)NC(=O)N[C:9]2=O)=[CH:2]1.ClC1C2[C:22](=[C:23]([F:28])[CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20]C=1.[OH-].[Na+].Cl>O>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:13]2[C:22]=1[N:21]=[CH:20][CH:9]=[C:8]2[CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: O=C1NC(=O)C(CCc2ccsc2)C(=O)N1
Reactant: Fc1cccc2c(Cl)ccnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc2c(CCc3ccsc3)ccnc12
Temperature: 150 °C
Yield: 100.1 %

Procedure:
A mixture of 1.85 g of 5-[2-(3-thienyl)ethyl]-barbituric acid and 1.5 g of 4-chloro-8-fluoroquinoline was heated to 150° C. for 11/4hours, then cooled. To the cooled mixture were added 2 g of NaOH and 35 ml of water, and the mixture was heated to reflux overnight. The mixture was cooled, then acidified to pH 1.5 with concentrated HCl, and heated gently for about 11/4 hours. After cooling the mixture, the product was extracted into CH2Cl2. The CH2Cl2 solution was filtered through phase separating paper, then evaporated in vacuo, giving about 2 g of oil residue. The residue was absorbed onto silica gel and chromatographed, eluting with CH2Cl2. Fractions containing product were combined, and the title product was crystallized. Recrystallization from petroleum ether/ CH2Cl2 gave 0.68 g of the title product. M.P. 96°-97° C.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2cccn2)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
To a solution of ethyl 4-fluorobenzoate (105 g) in DMSO (250 mL) were added pyrazole (34.0 g) and potassium carbonate (138 g), and the mixture was heated with stirring at 130° C. for 16 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (73.7 g).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[O:27]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccccc1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3Oc3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.15 g of phenol, 0.55 g of potassium carbonate and 2 ml of DMF was stirred at room temperature for one hour, and then stirred while heating at 50° C. for four hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.24 g of 2-(3-phenoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 38”).
Reaction SMILES: [ClH:1].[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.[C:21]1(NN)C=CC=CC=1>>[ClH:1].[CH3:21][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[CH2:2][NH:3][CH2:4][CH2:5][C:6]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]=2[CH:9]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Agent: Cl
Product: CCOC(=O)Cn1c2c(c3ccc(C)cc31)CNCC2

Procedure:
The title compound is prepared using a procedure analogous to Intermediate 1, substituting 3-methylphenylhydrazine for phenylhydrazine in Step 1a).