Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]=[N:9][C:8]=2[C:19]([F:22])([F:21])[F:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23](=O)[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl>O1CCCC1>[CH2:23]([N:16]1[CH2:15][CH2:14][N:13]([C:11]2[N:10]=[N:9][C:8]([C:19]([F:22])([F:21])[F:20])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=2)[CH2:18][CH2:17]1)[CH3:24]
Reactant: FC(F)(F)c1nnc(N2CCNCC2)cc1-c1ccccc1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN1CCN(c2cc(-c3ccccc3)c(C(F)(F)F)nn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
To a mixture of 4-phenyl-6-piperazin-1-yl-3-trifluoromethyl-pyridazine (E1) (0.15 g, 0.49 mmol) in tetrahydrofuran (5 ml), was added acetaldehyde (55 ml, 0.97 mmol). The reaction mixture was stirred at room temperature for 30 min., and then sodium triacetoxyborohydride (0.154 g, 0.73 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. Then, more acetaldehyde (55 ml, 0.97 mmol) and sodium triacetoxyborohydride (0.154 g, 0.73 mmol) were added and the mixture was stirred at room temperature for 4 h. Dichloromethane was then added and the mixture was extracted with a saturated solution of ammonium chloride. The organic phase was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography (silica gel; ethyl acetate/10% ammonia in methanol (7M) in dichloromethane 10:0 to 8:2). The desired fractions were collected, the solvent evaporated in vacuo, the residue dissolved in acetonitrile and converted into its hydrochloric acid salt by addition of a saturated solution of hydrochloric acid in diethyl ether. The white solid obtained was filtered and dried affording E2 (0.039 g, 21%). C17H19F3N4.HCl; free base requires 336; Found 337 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH2:14][C:13]2[C:8](=[C:9]([O:21][CH3:22])[C:10]([O:19][CH3:20])=[C:11]([O:17][CH3:18])[C:12]=2[O:15][CH3:16])[CH2:7]1)=[O:5])[CH3:2].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:31])[CH2:7][C:8]2[C:13](=[C:12]([O:15][CH3:16])[C:11]([O:17][CH3:18])=[C:10]([O:19][CH3:20])[C:9]=2[O:21][CH3:22])[CH2:14]1)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)C1(CCCCCCCC(=O)O)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCCCCCC(=O)N2CCOCC2)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
A THF (4.0 ml) suspension of 8-(2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl)octanoic acid (114 mg, 0.252 mmols), morpholine (0.110 ml, 1.26 mmols), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96.6 mg, 0.504 mmols) and 1-hydroxybenzotriazole monohydrate (77.2 mg, 0.504 mmols) was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, to which was added water. Then, this was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:1) to obtain the entitled compound (123 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]#[N:8].[CH2:9]([N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](=O)[CH3:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:20]1([N:16]([C:17](=[N:1][C:2]2[NH:6][CH:5]=[N:4][C:3]=2[C:7]#[N:8])[CH3:18])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)N(Cc1ccccc1)c1ccccc1
Reactant: N#Cc1nc[nH]c1N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(=Nc1[nH]cnc1C#N)N(Cc1ccccc1)c1ccccc1

Procedure:
5-Aminoimidazole-4-carbonitrile is condensed with N-benzyl-N-phenyl-acetamide in the presence of phosphoryl chloride in acetonitrile at room temperature to yield 5-[1-(N-phenyl-N-benzylamino)ethylideneamino]-imidazole-4-carbonitrile. Such is cyclized with sodium hydride in dioxane to yield 7-amino-N-phenyl-N-benzyl-3H-imidazo[4,5-b]pyridine-5-amine. Hydrogenolysis in ethanol with palladium on charcoal yields 7-amino-N-phenyl-3H-imidazo[4,5-b]pyridine-5-amine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1>>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:14][CH:15]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with p-toluidine to yield 2-[(4-methylphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([C:18](=[O:20])[CH3:19])=[CH:15][C:14]=3[CH:21]=2)=[CH:6][CH:5]=1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([OH:20])[CH3:19])=[CH:15][C:14]=3[CH:21]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(COc2ccc3oc(C(C)=O)cc3c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOc1ccc(COc2ccc3oc(C(C)O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of the obtained 1-{5-[(4-ethoxybenzyl)oxy]-1-benzofuran-2-yl}ethanone (6.95 g) in methanol (50 mL) was added sodium borohydride (1.04 g, 27.4 mmol) by small portions, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the solvent was evaporated. Ethyl acetate was added thereto, and the mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=3:2) to give the title compound (2.87 g, yield 67%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:21]=3[C:14]([C:15]3[C:20]=2[C:19]=1[CH:18]=[CH:17][CH:16]=3)=[CH:13][CH:12]=[CH:11]4.[C:22]1([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu]>[C:29]1([N:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH:7]=[CH:8][CH:9]=[C:10]5[C:21]=4[C:14]([C:15]4[C:20]=3[C:19]=2[CH:18]=[CH:17][CH:16]=4)=[CH:13][CH:12]=[CH:11]5)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Brc1ccc2c3cccc4cccc(c5cccc1c52)c43
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccc3c4cccc5cccc(c6cccc2c63)c54)cc1
Reaction time: 40 h

Procedure:
The following compounds were introduced into a vessel: (a) 3-bromoperylene; (b) diphenylamine; (c) potassium carbonate; (d) copper power; and (e) nitrobenzene. Then, the mixture was stirred at 200 degrees centigrade for 40 hours. After reaction has finished, nitrobenzene was removed under a reduced pressure. Then, chlorofom was added to the mixture, and filtered for removing inorganic materials. A filtrate was condensed, and then, impurities were removed by silica gel column chromatography employing ligroin. As a result, there was obtained a target material, 3-diphenylaminoperylene.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21])=[O:13].[C:22](=O)([O:26]CC)[O:23][CH2:24][CH3:25].Cl>C1COCC1>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([OH:21])=[C:14]([C:12](=[O:13])[CH2:11][C:22]([O:23][CH2:24][CH3:25])=[O:26])[CH:19]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1O
Temperature: -10 °C
Reaction time: 1 h
Yield: 407.9 %

Procedure:
A solution of lithium hexamethyldisilazide (800 mL of 1.0 M solution in THF, 800.0 mmol) was chilled to −78° C. under a nitrogen atmosphere. A solution of 5-chloro-2-hydroxyacetophenone (45.493 g, 266.67 mmol) in THF (130 mL) was added dropwise to the stirred solution over 0.5 hour. The reaction was held at −78° C. for 1 hour, warmed to −10° C. for 2 hours, warmed to 0° C. for 1 hour, then cooled to −78° C. Diethyl carbonate (35.54 mL, 34.65 g, 29.34 mmol) was added via syringe in one portion. The temperature was maintained at −78° C. for 0.5 hour, warmed to room temperature over 0.5 hour, and stirred for 3 hours. The crude reaction mixture was carefully poured over a mixture of rapidly stirred ice (1200 mL)/conc HCl (222 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo yielding an oil that began to crystallize. Hexanes (150 mL) was added and crystallization proceeded. The crystalline product was collected by vacuum filtration to afford the title compound (29.04 g, 45%) as tan crystalline needles: mp 71.8-73.1° C. 1H NMR (CDCl3/300 MHz) 7.63 (d, 1H, J=2.4 Hz), 7.45 (dd, 1H, J=8.9, 2.6), 6.98 (d, 1H, J=8.9 Hz), 4.25 (q, 2H, J=7.3 Hz), 3.98 (s, 2H), 1.29 (t, 3H, 7.3 Hz). FABLRMS m/z 249 (M+Li). EIHRMS m/z 242.0346 (M+, Calc'd 242.0346). Anal. Calc'd for C11H11ClO4: C, 54.45; H, 4.57. Found: C, 54.48; H, 4.62.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([SH:15])[N:9]=1.[CH3:16]I>CC(C)=O>[CH3:16][S:15][C:10]1[N:11]=[C:12]([CH3:14])[CH:13]=[C:8]([CH3:7])[N:9]=1
Reactant: CI
Reactant: Cc1cc(C)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1nc(C)cc(C)n1
Yield: 82.3 %

Procedure:
A suspension of potassium carbonate (27.6 g, 0.2 mol) in a solution of 4,6-dimethyl-2-mercaptopyrimidine (14 g, 0.1 mol) and methyl iodide (18.7 ml, 0.3 mol) in acetone (200 ml) was heated under reflux for 3 hours. The reaction mixture was allowed to cool before being filtered and then evaporated in vacuo. Distillation of the mixture at a pressure of 0.01 mmHg afforded 12.7 g 2-methylthio-4,6-dimethylpyrimidine as a white solid. A portion of this solid (4.42 g, 28.7 mmol) was dissolved in dichloromethane (200ml) and m-chloroperoxybenzoic acid (50%, 22.8 g, 66.0 mmol) was added in portions. The resulting mixture was stirred for a period of 5 days at the end of which it was first filtered and then evaporated in vacuo. Purification by flash column chromatography upon silica gel using diethyl ether as eluant afforded 3.35 g 2-methylsulphonyl-4,6-dimethylpyrimidine as a white solid, m.pt., 81° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C1(O[C:13]2[C:14](=[O:26])[N:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:16]=[CH:17][N:18]=2)CCCCC1.C([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[Cl:3][C:13]1[C:14](=[O:26])[N:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:16]=[CH:17][N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c(OC2CCCCC2)nccn1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: O=c1c(Cl)nccn1-c1ccc(F)cc1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 94.1 %

Procedure:
Phosphorus oxychloride (0.94 mL, 10 mmol) was added to a solution of 3-cyclohexyloxy-1-(4-fluoro-phenyl)-1H-pyrazin-2-one (0.97 g, 3.36 mmol) in DCE (10 mL). The reaction mixture was stirred at 160° C. for 15 minutes under microwave irradiation. The reaction was poured into ice-water, then basified with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 3-chloro-1-(4-fluoro-phenyl)-1H-pyrazin-2-one (0.71 g, 95% yield) that was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C@@H:11]([CH2:14][OH:15])[O:10][C:9]=2[CH:16]=1)(=[O:4])=[O:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:15][CH2:14][C@H:11]2[O:10][C:9]3[CH:16]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)O[C@H](CO)CO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Yield: 87.5 %

Procedure:
Preparation according to Preparation 5 using [[(2R)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (2.1 g, 8.6 mmol), p-toluenesulfonyl chloride (2.5 g, 12.8 mmol), TEA (1.8 ml, 12.8 mmol) and 4-DMAP (1.0 g, 8.6 mmol) and DCM (dry, 20 ml). DCM (50 ml) was added and the solution was washed with HCl (100 ml, 1 N), water (100 ml) and brine (100 ml) and was evaporated to dryness to give the title compound (3.0 g). MS m/z (rel. intensity, 70 eV) 398 (M+, 49), 226 (bp), 225 (24), 213 (30), 91 (68).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.Cl>ClCCl>[CH3:1][C@@H:2]1[N:7]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Yield: 90.9 %

Procedure:
To a solution of 1,1-dimethylethyl(3S)-3-methyl-1-piperazinecarboxylate (500 mg, 2.497 mmol) in dichloromethane (20 ml) was added DIPEA (0.654 ml, 3.74 mmol) and then portionwise addition of 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (0.445 ml, 2.62 mmol) at room temperature and the resultant mixture stirred under an atmosphere of argon for 16 hours. The reaction was worked up by the addition of 1M HCl solution (75 mL) and dichloromethane (75 mL), the layers were separated and the organic layer was then washed with 2M NaOH solution (75 mL). The organic phase was separated, dried (MgSO4) and concentrated to dryness to give 1,1-dimethylethyl(3S)-3-methyl-4-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)-1-piperazinecarboxylate (963 mg, 2.269 mmol). This was dissolved in 1,4-dioxane (4 mL), HCl (4M in 1,4-Dioxane) (2.269 mL, 9.08 mmol) was added and the resultant mixture stirred under an atmosphere of argon for 2 h. After this time a white precipitate had formed so methanol (5 ml) was added to solubilize the precipitate and the reaction stirred for a further 30 min. The reaction was concentrated to dryness giving a white solid which was triturated with Et2O and the solid isolated by filtration under vacuum to give the title compound (585 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:19]([OH:22])[C:20]#[CH:21]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:21]#[C:20][CH2:19][OH:22])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CC1CCCC1)c1ccc(C#CCO)cc1
Temperature: 70 °C
Yield: 91.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (2.15 g, 6.00 mmol) and triethylamine (6 mL, 0.04 mmol) in N,N-dimethylformamide (6 mL) was treated with propargyl alcohol (0.87 mL, 15.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (30 mg, 0.15 mmol) and bis(triphenylphosphine)palladium (II) chloride (45 mg, 0.06 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (120 mL) and washed with a half-saturated aqueous sodium chloride solution (1×60 mL). The resulting aqueous layer was back extracted with ethyl acetate (1×120 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-propionic acid methyl ester (1.57 g, 91%) as an amber oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[CH3:13][N:14]([CH3:29])[CH2:15][CH2:16][O:17][C:18]1[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:24][C:21]2[CH:22]=[N:23][C:18]([O:17][CH2:16][CH2:15][N:14]([CH3:29])[CH3:13])=[C:19]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CN(C)CCOc1ncc(N)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCOc1ncc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 16 h
Yield: 63.6 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (100 mg, 0.429 mmol), 6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-amine (107 mg, 0.429 mmol) and HATU (245 mg, 0.644 mmol) in DCM (15 mL) was added DIEA (0.225 mL, 1.287 mmol). The resulting mixture was stirred at 20° C. for 16 h. The mixture was washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (DCM/MeOH=10/1) to yield a brown oil of 2-(4-bromo-2-fluorophenyl)-N-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)acetamide (130 mg, 0.273 mmol, 63.7% yield): 1H NMR (400 MHz, CD3OD) δ 8.51 (d, J=2.0 Hz, 1H), 8.29 (d, J=2.4 Hz, 1H), 7.38-7.26 (m, 4H), 4.62 (t, J=5.4 Hz, 2H), 3.75 (s, 2H), 3.08 (t, J=5.2 Hz, 2H), 2.56 (s, 6H); ES-LCMS m/z 464.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)=[O:13])[CH:6]=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:24]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCC(O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(O)CC3)c2)c(F)c1
Reaction time: 2 h

Procedure:
4-(2-Fluoro-4-nitrophenoxy)-2-[(4-hydroxypiperidin-1-yl)carbonylamino]pyridine (169 mg) was dissolved in methanol (5 ml)-tetrahydrofuran (5 ml), and then 10% palladium carbon (200 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring for 2 hrs. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with ethyl acetate. The filtrate was concentrated under a reduced pressure to provide the titled compound (168 mg, quantitatively) as pale yellow powder.
Reaction SMILES: [I-:1].[Na+].[CH2:3](Br)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[CH2:3]([I:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCBr
Reactant: [I-]
Agent: [Na+]
Product: CCCCCCCCI
Yield: 100 %

Procedure:
N-substituted perhydro-s-triazine compounds can be used to increase the solubility of alkali or alkaline earth metal salts in an organic medium. Increasing the solubility of such salts catalyzes the reaction between the salts and other components of the organic medium. For example, 5 percent of a tris(n-octylpolyoxyethylene)-N,N',N"-perhydro-s-triazine compound catalyzes the reaction between sodium iodide and n-octyl bromide at 80° C. for 1 hour to form 100 percent yield of n-octyl iodide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])(C(OCC)=O)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Ba+2].[OH-]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCC1(C(=O)OCC)N=C(c2ccc(Cl)cc2)c2cc(CC)sc2-n2c(C)nnc21
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1cc2c(s1)-n1c(C)nnc1C(CCC(=O)O)N=C2c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 3.9 %

Procedure:
4-(4-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (10 g) is dissolved in diethyl carbonate (150 ml) in a nitrogen stream, and 60% sodium hydride (2.0 g) is added with stirring at room temperature. The mixture is refluxed under heating for 2 hours and cooled to 50° C. with ice water. Ethyl acrylate (5.4 ml) is added. After stirring at 50° C. for 3 hours, the reaction mixture is poured into ice water (1 l) and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate:methanol=100:l) to give 3.2 g of (±)-ethyl 3-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)propionate as an oil. (±)-Ethyl 3-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-6-yl)propionate (3.2 g) is dissolved in a mixture of ethanol (90 ml) and water (30 ml), and barium hydroxide 8 hydrate (7.8 g) is added. The mixture is refluxed under heating for 4 hours. After the completion of the reaction, ethanol is distilled away under reduced pressure and adjusted to pH 1 with 6N hydrochloric acid. The mixture is stirred for 30 minutes and adjusted to pH 4 with a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The organic layer is washed with a saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is crystallized from ethyl acetate and isopropyl ether to give 0.1 g of (±)-3-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-6-yl)propionic acid as brown crystals, melting point 210°-212° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[C-:17]#[N:18].[Na+]>C(O)C.O>[F:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:17]#[N:18]
Reactant: [C-]#N
Reactant: Fc1cccc(Oc2ccccc2CCl)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccccc1Oc1cccc(F)c1

Procedure:
1-(Chloromethyl)-2-(3-fluorophenoxy)benzene (26.5 g.) was dissolved in 300 ml of ethanol; a solution of sodium cyanide (7.8 g.) in 15 ml of water was added, and the resulting mixture was heated to reflux overnight. The ethanol was evaporated, the residue taken up in water, extracted with ether and the combined ether extracts were dried and concentrated to give the title compound. ##STR13##