Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]1=[O:22].[OH-:23].[Na+]>O1CCOCC1>[C:16]1([CH2:15][CH2:14][CH2:13][C@H:10]([C@@H:11]([NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH3:12])[C:9]([OH:22])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [OH-]
Reactant: C[C@H]1[C@@H](CCCc2ccccc2)C(=O)N1OC1CCCCO1
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H](NOC1CCCCO1)[C@@H](CCCc1ccccc1)C(=O)O
Reaction time: 20 h
Yield: 99 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(3-phenyl-1-propyl)-4-methylazetidin-2-one (20.5 g, 67.6 mmol) in dioxane (220 mL) is added 1 M aqueous sodium hydroxide (102 mL). The solution is stirred at 23.degree. C. for 20 h, then extracted with hexanes (200 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate solution, and is extracted with two 300 mL portions of ethyl acetate. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(3-phenyl-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid as an oil (21.5 g, 99% yield).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].C1(C)C=CC=CC=1.O>C(OCC)(=O)C>[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc([N+](=O)[O-])c(NCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 3-fluoro-4-nitrobenzoic acid (5.20 g), 2,4-dichlorobenzyl-amine (14.8 g) and toluene (35 ml) was refluxed under heating for 24 hr. The mixture was heated to room temperature, and water and ethyl acetate were added. The mixture was stirred and precipitated crystals were collected by filtration. The chloroform layer of the filtrate was separated and the solvent was distilled away. Ether was added to the residue and the precipitated crystals were collected by filtration. The crystals were combined, washed with ether and dried to give 3-(2,4-dichlorobenzyl-amino)-4-nitrobenzoic acid. Sulfuric acid (2.3 g) was added thereto, and the mixture was refluxed under heating in ethanol for 6 hr. The reaction mixture was concentrated and poured into a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with ethyl acetate, washed with saturated brine and dried. The solvent was distilled away and the residue was crystallized from a mixed solvent of ethyl acetate and hexane. The crystals were collected by filtration and dried to give the objective compound (4.0 g).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([C:12]2[CH:13]=[N:14][C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)=[O:11])=[CH:2]1.[BH4-].[Na+].O>CN(C)C=O.C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]([C:12]2[CH:13]=[N:14][C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)[OH:11])=[CH:2]1
Reactant: O=C(c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)c1c[nH]c2ncccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: OC(c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Into a round bottom flask was added (1H-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-methanone P-0017 (210.0 mg, 0.53 mmol) and sodium tetrahydroborate (80.0 mg, 2.11 mmol), dissolved in N,N-dimethylformamide (5.0 mL) and ethanol (20.0 mL). The reaction was stirred at room temperature overnight, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage (dichloromethane/methanol 1:20) to give compound 14 (63 mg, yield=30%) as a white solid. MS (ESI) [M+H+]+=399.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:20][OH:21].[C:22](Cl)(=[O:24])[CH3:23]>ClCCl>[F:1][C:2]1[C:3]([CH2:20][OH:21])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:19]2)=[N:12][CH:13]=1
Reactant: CC(=O)Cl
Reactant: OCc1cccc(-c2cnc(C3CCNCC3)nc2)c1F
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ncc(-c3cccc(CO)c3F)cn2)CC1
Reaction time: 3 h
Yield: 98.1 %

Procedure:
{2-Fluoro-3-[2-(piperidin-4-yl)pyrimidin-5-yl]phenyl}methanol (80 mg) was mixed with dichloromethane (1.6 ml), and TEA (85 mg) and acetyl chloride (48 mg) were added thereto at 0° C. The reaction mixture was concentrated under reduced pressure, the residue was mixed with MeOH, and a 1M aqueous NaOH solution (0.8 ml) was added thereto, followed by stirring for 3 hours. 1M hydrochloric acid was added to the reaction mixture, and CHCl3/water was added to the reaction liquid. The aqueous layer was extracted with CHCl3, and the prepared organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 1-(4-{5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperidin-1-yl)ethanone (90 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[CH2:6]1[CH2:10][O:9][C:8]2[CH:11]=[CH:12][C:13]3[CH2:14][CH:15]=[C:16]([CH2:18][CH2:19][NH2:20])[C:17]=3[C:7]1=2.C(N(CC)CC)C>CN(C)C=O>[CH2:6]1[CH2:10][O:9][C:8]2[CH:11]=[CH:12][C:13]3[CH2:14][CH:15]=[C:16]([CH2:18][CH2:19][NH:20][C:1](=[O:3])[CH3:2])[C:17]=3[C:7]1=2
Reactant: NCCC1=CCc2ccc3c(c21)CCO3
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NCCC1=CCc2ccc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
Acetyl chloride (0.24 g, 3.03 mmol) was slowly added dropwise to an ice-cooled solution of 2-(1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydro-chloride (0.6 g, 2.52 mmol) and triethylamine (0.64 g, 6.31 mmol) in N,N-dimethylformamide (60 mL). After overnight stirring at room temperature, the reaction mixture was concentrated and poured into water, and the organic matter was extracted with ethyl acetate. The extract was washed with a satruated aqueous sodium chloride solution and water and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate:methanol=98:2) and further recrystallized from ethyl acetate to give 425 mg (yield: 70%) of the target compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C1COCC1>[CH3:30][S:31]([O:29][CH2:28][C@H:25]1[CH2:26][CH2:27][N:23]([C:21]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][N:19]=3)[CH:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:8][CH:9]=3)[N:22]=2)[CH2:24]1)(=[O:33])=[O:32]
Reactant: OC[C@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)OC[C@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-(1-(7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-yl)pyrrolidin-3-yl)methanol (compound 163, 500 mg, 1.27 mmol) in THF (15 mL) were added MsCl (200 mg, 1.6 mmol) and TEA (370 mg, 3.7 mmol). The mixture was stirred for 4 hours at room temperature and concentrated in vacuo. The residue was washed by H2O and EtOAc to give the title compound. MS (m/z): 470 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[CH3:23][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH3:23])[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Sc2c(C)n(C)c3cc(Cl)ccc23)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.0752 g, 0.23 mmol) was dissolved in DMF:THF (1:1, 4 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide solution (0.500 mL, 0.5 mmol, 1.0M in hexanes) was added. After 1 hour, iodomethane (11 μL, 0.18 mmol) was added and the reaction was allowed to warm to room temperature over 30 minutes then submitted to aqueous workup. Purification by silica gel chromatography (0-100% EtOAc in hexanes) provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[C:12]1([N:18]2[C:22]3([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:21](=[O:28])[NH:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:25]1[CH2:24][CH2:23][C:22]3([N:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:19][NH:20][C:21]3=[O:28])[CH2:27][CH2:26]1)[CH2:6][CH2:5]2
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C1CCc2cc(Cl)ccc21
Product: Cl
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCc3cc(Cl)ccc31)CC2

Procedure:
The title compound, m.p.>250° C. and MS: m/e=382.2 (M+H+) was prepared in accordance with the general method of example 34 from 5-chloro-2,3-dihydro-1H-inden-1-one and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1.[CH2:29](N)[CH2:30][NH2:31].CC1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[NH:26]1[CH2:29][CH2:30][N:31]=[C:25]1[C:24]1[CH:23]=[CH:22][C:21]([S:18]([C:5]2[C:6]([NH:8][C:9]3[C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[CH:13][C:14]=3[CH3:15])=[N:7][C:2]([CH3:1])=[N:3][CH:4]=2)(=[O:20])=[O:19])=[CH:28][CH:27]=1
Reactant: NCCN
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(C#N)cc2)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(C3=NCCN3)cc2)c(C)c1
Temperature: 25 °C
Yield: 15.3 %

Procedure:
A mixture of 4-[2-methyl-4-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-sulfonyl]-benzonitrile (83 mg, 0.21 mmol), prepared by the method described in Example 22, ethylenediamine (0.042 mL, 0.63 mmol), p-TsOH.H2O (59 mg, 0.31 mmol) and toluene (4 mL) was heated at reflux under N2 overnight and then cooled to room temperature. Saturated aqueous NaHCO3 was added, and the mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (75:25 EtOAc/MeOH) to provide the target compound (14 mg, 15%) as a white solid: mp 240–242° C.; 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 1H), 8.27 (br s, 1H), 8.00 (d, J=8.5 Hz, 2H), 7.95 (d, J=8.5 Hz, 2H), 6.92 (s, 2H), 4.80 (br s, 1H), 3.83 (s, 4H), 2.40 (s, 3H), 2.30 (s, 3H), 2.01 (s, 6H); ESI MS m/z 436 [(M+H)+, calcd for C23H26N5O2S, 436.2].
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][CH:10](OS([O-])(=O)=O)[CH2:11][CH:12]([CH3:14])C)[CH2:6]C.[Na+]>O>[CH2:1]=[CH:2][CH:3]=[CH2:4].[CH2:14]=[CH:12][C:11]1[CH:6]=[CH:5][CH:8]=[CH:9][CH:10]=1
Reactant: CCCCC(CC)CCC(CC(C)C)OS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: C=CC=C
Product: C=Cc1ccccc1

Procedure:
The material was prepared by dispersing 0.80 g Tergitol TMN-06 in 1481 g deionized water with an air mixer. To this was then added 1159 g of ground crystalline silicotitanate (150 g, 13.0% solids) (IONSIV IE 910) with agitation. Slowly to this was added 150.1 g Goodrite 1800×73 (39% solids, 58.5 g) with stirring. This mixture was mixed for 1 hour with an air mixer. The slurry was spray dried using a Niro Atomizer, (Serial number #2402) at 35 mL/min. Spray drying conditions were as follows:
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH3:23])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])(C)(C)C.Cl.[C:25]([O:29][C:30]([NH:32][C@H:33](C(O)=O)[CH2:34][C:35]1[N:36]=[CH:37][S:38][CH:39]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[C:25]([O:29][C:30]([NH:32][C@H:33]([C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH3:23])[CH2:18]1)[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:7])[CH2:34][C:35]1[N:36]=[CH:37][S:38][CH:39]=1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)[C@H](Cc2cscn2)NC(=O)OC(C)(C)C)OC1=O
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 70.2 %

Procedure:
A mixture of 513 mg (1.58 mmole) of (3R, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 2) and 20 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 65 minutes. At the end of this time, the solvent was stripped from the mixture by distillation under reduced pressure, and diethyl ether was added to the residue. The resulting mixture was then concentrated by evaporation under reduced pressure. This operation was repeated three times, in total, after which the final residue was dried by evaporation under reduced pressure for 8 hours. At the end of this time, the dried materials were suspended in 30 ml of anhydrous tetrahydrofuran, and 460 mg (1.69 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to the suspension. 0.27 ml (1.69 mmole) of 95% diethyl cyanophosphonate and 0.88 ml (6.34 mmole) of triethylamine were then added to the mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred at room temperature for 6 hours, after which the solvent was removed by distillation under reduced pressure. The resulting residue was mixed with 50 ml of water to deposit gummy materials. These were collected by filtration and washed with water. They were then dissolved in methylene chloride. The resulting solution was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under reduced pressure. The residue was recrystallized from diisopropyl ether to afford 532 mg of the title compound as white crystals, melting at 118°-120° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=O)[O:17]C2C=CC=CC=2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[NH3:27]>O>[F:26][C:2]([F:1])([F:25])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH2:27])=[O:17])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:6])([F:7])[F:5]
Reactant: N
Reactant: O=C(Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)Oc1ccccc1
Solvent: O
Product: NC(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine 6.0 g (16 mmole) of phenyl N-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]carbamate (Example 12) and 65 ml of NH3 saturated ethanol. After 1/2 hour, pour the reaction mixture into 150 ml of H2O. Concentrate, cool to 0° C and filter off the white solid. Obtain 5.5 g of N-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]urea; m.p. 181°-183° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:36][C:37]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](O)=[O:40]>C(Cl)(Cl)Cl>[F:36][C:37]1[C:45]([C:46]([F:47])([F:48])[F:49])=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(C(F)(F)F)c2F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3.66 g of 1-Boc-piperazine, 4.53 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.61 g of 1-hydroxybenzotriazole, 4.50 g of 2-fluoro-3-(trifluoromethyl)benzoic acid and 40 ml of chloroform was stirred at room temperature for 4 hours. The reaction mixture was diluted with chloroform and then was washed with water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=4/1 to 2/1) to give the title compound.
Reaction SMILES: [O:1]([CH2:8][CH2:9]N1CCC(CNC(C2SC3N4C(=CN=C4C=CC=3)C=2)=O)CC1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].[O:37](C(O)C)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[S:33]([O:35][CH2:9][CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:37])(=[O:34])[CH3:32]
Reactant: O=C(NCC1CCN(CCOc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccccc1
Reaction time: 0.58 h

Procedure:
Synthesis of N-[1-(2-phenoxyethan-1-yl)piperidin-4-ylmethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide Under nitrogen gas, 0.37 ml (4.78 mM) of methanesulfonyl chloride was added to a solution of 0.44 g (3.18 mM) of phenoxyethanol and 0.89 ml (6.39 mM) of triethylamine in methylene chloride (6 ml) at 0° C. and the mixture was stirred at the prevailing temperature for 35 minutes. The reaction was stopped by adding saturated aqueous solution of sodium hydrogen carbonate and the reaction mixture was extracted with diethyl ether. The organic layer was washed serially with water and saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide 0.6989 g (<3.18 mM) of phenoxyethyl mesylate. To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.2 mM) of triethylamine in ethanol (6.0 ml) was added 0.6989 g (<3.18 mM) of the above phenoxyethyl mesylate at room temperature and the mixture was refluxed under nitrogen for 17 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 30-40%) to provide the title compound.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]1([CH:20]([NH2:25])[C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.CC(C)=O>[C:14]1([CH:20]([NH:25][C:2]([NH:3][C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[S:1])[C:21]([F:23])([F:24])[F:22])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NC(c1ccccc1)C(F)(F)F
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccccc1
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC(=S)NC(c1ccccc1)C(F)(F)F)c1ccccc1

Procedure:
8.2 g ammonium thiocyanate are dissolved in 54 ml water and the resulting solution is cooled to about 0°. The temperature is kept at this temperature during the addition of a solution of 11.5 ml benzoyl chloride in 10.5 ml acetone thereto. The temperature of the reaction mixture is allowed to revert to about 30° then the mixture is heated to reflux for 10 mn. A solution of α-phenyl trifluoroethylamine in 110 ml. acetone is thereafter added portionwise for 1 hour while heating the mixture at reflux. The heating is maintained for a further period of 11/2 hour then let to revert to ambient temperature. The solvent is distilled off. The dry residue is taken up in 250 ml water. The aqueous solution is extracted 3 times with 200 ml ether. The organic phases are united, washed with water until the washings are free of chlorine ions, filtered and dried on sodium sulphate. The solvent is evaporated off, under reduced pressure and 34.1 g of raw product are recovered. The compound is purified by recrystallizing it from hexane. The pure N-(α-phenyl trifluoroethyl) N'-benzoyl thio Urea melts at 55°-60°.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9](=O)[C:10](=[N:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]#[N:12])CCOCC1.O.[NH2:23][NH2:24].[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1.NN>C(OCC)C>[N:1]1([CH2:7][CH2:8][C:9]2[C:10](=[N:13][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([NH2:12])=[N:23][N:24]=2)[CH2:25][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1CCOC1
Reactant: N#CC(=NNc1ccccc1)C(=O)CCN1CCOCC1
Reactant: NN
Solvent: O
Solvent: CCOCC
Product: NC1=NN=C(CCN2CCOCC2)C1=NNc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
To a suspension of 5-morpholin-4-yl-3-oxo-2-(phenylhydrazono)pentanenitrile (1.2 mmole) in 15 mL of diethyl ether was slowly added a solution of hydrazine hydrate (2.4 mmol) in 2 of THF which resulted in a clear red solution. After 2 hours, another portion of hydrazine (2.4 mmol) was added at which point some yellow precipitate was observed. The reaction was stirred at ambient temperature overnight. The solid was collected by filtration, purified by recrystalization from ethanol and dried in vacuo to yield 150 mg (41%) of the title compound. MS (m/z, ES+): 301 (M+1, 100%). 1H NMR (ppm, 300 MHz, DMSO-d6) δ 11.63 (br s, 1H), 7.67 (m, 2H), 7.44 (m, 2H), 7.29 (m, 1H), 6.97 (br s, 2H), 3.55 (m, 4H), 2.93 (m, 2H), 2.66 (m, 2H), 2.43 (m, 4H).
Reaction SMILES: [CH:1]1[CH:6]=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:2]=1.Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH:26]=1.CN(C=[O:37])C>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]1[CH:26]=[C:21](/[CH:2]=[CH:1]/[CH:6]=[O:37])[CH:22]=[N:23][CH:24]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)C=O
Reactant: Brc1cncc(-c2ccccn2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: O=C/C=C/c1cncc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of Pd2(dba)3 (36 mg, 0.04 mmol) and PPh3 (triphenylphosphine) in DMF (degassed, 2.0 mL) was allowed to stir for 5 min. at 25° C. 1,1′-Diethyl 3-(tributyltin)-propenylacetal (0.44 g, 1.27 mmol) and 3-bromo-5-(2-pyridinyl)-pyridine (100 mg, 0.42 mmol) were added and the resulting mixture was warmed to 80° C. After 18 h, the reaction mixture was allowed to cool to 25° C., diluted with ethyl acetate (100 mL), washed with brine (1×50 mL) and concentrated in vacuo. The residue was dissolved in 2N aqueous HCl (2.0 mL) and allowed to stir for 30 min. The reaction mixture was neutralized by the addition of sodium bicarbonate until the pH ˜7, diluted with ethyl acetate (100 mL), washed with brine (1×50 mL), and concentrated in vacuo. Purification by flash chromatography (0-50% EtOAc/hexanes) afforded the title compound (10 mg) as a white solid. MS 211 (M+H)+.