Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[C:13]1[N:18]=[C:17](S)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=1>CN(C)C=O>[Cl:3][C:17]1[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]([C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[F:6])[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(S)nc(-c2ccncc2F)cc1=O
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Temperature: 60 °C
Yield: 73.3 %

Procedure:
After one hour stirring of a solution of phosphorus oxychloride (45 g, 293 mmol) in dimethylformamide (450 ml) at room temperature, 6-(3-fluoropyridin-4-yl)-2-mercapto-3-methyl-3H-pyrimidin-4-one (46.3 g, 195 mmol) was added and heated at 60° C. for 2 hours. The resulting suspension was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was washed by hexane to furnish 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (34.2 g, 143 mmol, 73%) as white crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[N:6][NH:5][C:4]1=S)[CH3:2].[OH:13]O>[OH-].[Na+]>[CH2:1]([N:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[N:6][NH:5][C:4]1=[O:13])[CH3:2]
Reactant: CCn1c(C(F)(F)F)n[nH]c1=S
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(C(F)(F)F)n[nH]c1=O
Reaction time: 6 h
Yield: 58 %

Procedure:
9.9 g (0.05 mol) of 4-ethyl-5-trifluoromethyl-2,4-dihydro-3H-1,2,4-triazole-3-thione and 50 ml of 2.5-molar sodium hydroxide solution are introduced. 17 ml (0.165 mol) of 30% strength hydrogen peroxide solution are added dropwise in the course of 20 minutes at a maximum temperature of 40° C. to 50° C. (cooling), stirring is continued for 6 hours at 40° C., the excess of hydrogen peroxide is removed by adding sodium hydrogen sulphite, and the mixture is acidified using concentrated hydrochloric acid and refluxed for 10 hours. When cold, the mixture is poured into ice-water, this is extracted repeatedly using dichloromethane, the combined organic phases are dried over sodium sulphate, and the solvent is evaporated on a rotary evaporator. 5.2 g (58% of theory) of 4-ethyl-5-trifluoromethyl-2,4-dihydro-3H-1,2,4-triazol-3-one of melting point 53° C. are obtained.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1>[C:2]1([CH:1]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 89 %

Procedure:
7.05 g (0.05 mol) of benzoyl chloride, 6.5 g (0.0625 mol) of styrene, 8.65 g (0.05 mol) of tri-n-butylamine, 0.1122 g (0.0005 mol) of palladium acetate and 100 ml of p-xylene are introduced into a 250 ml flask and heated to 120° C., with stirring. A slight evolution of gas is observed. After the mixture has been stirred for 2 hours at 120° C., it is cooled and extracted by shaking with 2×25 ml portions of 2 N hydrochloric acid, and the organic phase is dried with magnesium sulfate. The p-xylene is distilled off and the residue is recrystallised from ethanol. 8.0 g (0.0445 mol) of stilbene are obtained as a colourless, crystalline compound, corresponding to a yield of 89% of theory; melting point 125° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[C:18]1[CH:25]=[C:24]([C:26]([NH2:34])([C:28]2[N:29]([CH3:33])[CH:30]=[N:31][CH:32]=2)[CH3:27])[CH:23]=[CH:22][C:19]=1[C:20]#[N:21]>>[NH2:34][C:26]([C:24]1[CH:25]=[CH:18][C:19]([C:20]#[N:21])=[C:22]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])[CH:3]=2)[CH:23]=1)([C:28]1[N:29]([CH3:33])[CH:30]=[N:31][CH:32]=1)[CH3:27]
Reactant: Cn1cncc1C(C)(N)c1ccc(C#N)c(F)c1
Reactant: O=S(=O)(c1cccc(O)c1)N1CCOCC1
Product: Cn1cncc1C(C)(N)c1ccc(C#N)c(Oc2cccc(S(=O)(=O)N3CCOCC3)c2)c1

Procedure:
Using the methods described in Example 24A, but substituting 3-hydroxybenzenesulfonylmorpholine (0.015 g, 0.061 mmol) and 2-fluoro-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile (as described in Example 24A, Step F), the title compound was prepared.
Reaction SMILES: [NH2:1][S:2]([N:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6]1)(=[O:4])=[O:3].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:60]1[CH:65]=[C:64]([O:66][CH3:67])[N:63]=[C:62]([S:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[C:71]=2[F:77])[N:61]=1.[Cl-].[NH4+]>O1CCOCC1.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]>[F:77][C:71]1[C:72]([F:76])=[CH:73][CH:74]=[CH:75][C:70]=1[CH2:69][S:68][C:62]1[N:61]=[C:60]([NH:1][S:2]([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6]2)(=[O:3])=[O:4])[CH:65]=[C:64]([O:66][CH3:67])[N:63]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(S(N)(=O)=O)CC1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(NS(=O)(=O)N2CCCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of tert-Butyl 4-(aminosulfonyl)-1,4-diazepane-1-carboxylate (the product of example 75, 0.277 g), tris(dibenzylideneacetone)-dipalladium (0) (45 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (24 mg), cesium carbonate (0.242 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of example 35 step i, 0.15 g) in anhydrous dioxane (6 ml) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 15 min. Saturated aqueous ammonium chloride was added and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica using a 1:19 to 3:7 mixture of EtOAc and iso-hexane as eluent to give the subtitle compound as a yellow oil. Yield: 0.223 g
Reaction SMILES: CS(C)=O.[C:5](=O)([O-])[O-].[K+].[K+].[C:11]1([C:17]2[NH:18][C:19]3[C:24]([C:25]=2[C:26](=[O:28])[CH3:27])=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.IC>O>[CH3:5][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]([C:26](=[O:28])[CH3:27])=[C:17]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1c(-c2ccccc2)n(C)c2ccccc12
Reaction time: 0.67 h
Yield: 85 %

Procedure:
Dimethylsulphoxide (12 ml) and potassium carbonate (3.31 g) were stirred for 10 min. and then 1-(2-phenyl-1H-indol-3-yl)-1-ethanone (1.41 g) was added and stirring was continued for a further 40 min. Iodomethane (0.75 ml) was added and the mixture was stirred for 2.75 h. Water (30 ml) was added and the mixture was extracted with ether (3×40 ml). The combined organic extracts were washed with water (4×40 ml), dried, and evaporated to leave an oil which was crystallised from cyclohexane to give the title compound (1.27 g), m.p. 76°-77°.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1.C(OCC)(=O)[CH2:29][C:30]([O-:32])=[O:31].[Li+].[OH-].O.[ClH:40]>C1COCC1.CS(C)=O.CO>[ClH:40].[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][NH:2][CH:1]4[CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN=C4)no2)cc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNC4CC(=O)O)no2)cc1C#N

Procedure:
A solution of 5-[3-(3,4-dihydro-5-isoquinolinyl)-1,2,4-oxadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile (Preparation 8, 96.2 mg, 0.268 mmol) and mono ethyl malonate (95 μl, 0.805 mmol) in THF (2 mL) was irradiated in the microwave to 120° C. for 10 min. Concentration gave a yellow oil that was purified by MDAP to two fractions containing both the desired carboxylic acid plus the corresponding ethyl ester. The fractions were combined and redissolved in MeOH-THF-water (1:1:1, 1.5 mL). LiOH (9.7 mg, 0.403 mmol) was added and the solution irradiated to 100° C. for 18 min. More LiOH (4.2 mg, 0.175 mmol) and water (300 μl) were added and the solution irradiated to 100° C. for 3 min. The reaction mixture was acidified to pH2 with 2M aqueous HCl and the resulting precipitate filtered to give a white solid. This was dissolved in DMSO-MeOH, added to an SCX cartridge, eluting with methanolic ammonia. Concentration gave a white solid, that was suspended in 1M aqueous HCl and irradiated at 100° C. for 5.5 h. The white precipitate was filtered and dried in vacuo overnight to give the title compound as a white solid (25.5 mg). 1H NMR (400 MHz, CDCl3) δ 9.56 (2H, br. S), 8.52 (1H, d), 8.41 (1H, dd), 8.00 (1H, d), 7.61 (1H, d), 7.57 (1H, d), 7.52 (1H, t), 5.01-4.94 (2H, m), 1.39 (6H, d), remaining aliphatic signals obscured by solvent peaks; m/z (ES) 419 [M+H]+.
Reaction SMILES: Cl.[NH2:2]O.[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH:13]=O)[CH2:8][CH2:7][CH2:6][CH2:5]1>C(OC(=O)C)(=O)C>[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[C:13]#[N:2])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NO
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C#N)cc1OC1CCCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Hydroxylamine hydrochloride (3.82 g) is added to a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (11.0 g) in acetic anhydride (30 mL) and the suspension heated in an oil bath at 100° C. until refluxing starts. The heating is then removed while the exothermic reaction refluxes gently. Heating at 100° C. is then continued for a further 1 hour. The dark solution is concentrated and the crude product dissolved in cyclohexane (200 mL). The solution is washed with 5% sodium bicarbonate solution (2×50 mL), water (2×50 mL) and brine (50 mL), and dried over magnesium sulfate. Upon evaporation, an amber oil (11.8 g) that is purified by flash chromatography (dichloromethane as eluant on silica column) gives 3-cyclopentyloxy-4-methoxybenzonitrile (8.6 g) as a pale yellow oil. [Elemental analysis: C,71.7; H,6.93; N,6.47%; calculated for C13H15NO2 : C,71.87; H,6.96; N,6.45%.].
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[CH:5]2>CCO.[Pd]>[NH2:13][C:3]1[C:2]([CH3:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[N:6][NH:7][C:8]2=[O:12]
Reactant: Cc1ccc2c(=O)[nH]ncc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(=O)[nH]ncc2c1N
Temperature: 50 °C
Reaction time: 144 h
Yield: 99.1 %

Procedure:
To a suspension of 6-methyl-5-nitrophthalazin-1(2H)-one (9.446 g, 46 mmol) in EtOH (1000 ml) charged to a 2000 mL round bottom flask, palladium, 10 wt. % on activated carbon (0.490 g, 0.46 mmol) was added. The reaction mixture was stirred at 50° C. for 6 days under H2 (1 atm). When complete, the reaction mixture was filtered through a small pad of celite, washing with excess EtOH and some DMF. The liquid was then concentrated under vacuum to give 5-amino-6-methylphthalazin-1(2H)-one (7.99 g, 99% yield) as a yellow solid. MS (M+H)+ 176.
Reaction SMILES: N=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[NH:8][C:9]([N:11]1C=CN=C1)=[S:10].Cl[CH2:17][C:18]1[NH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][N:22]=1>CN(C=O)C>[C:23]1([C:20]2[N:19]=[C:18]([CH2:17][S:10][C:9]3[N:11]=[C:4]4[CH:5]=[CH:6][CH:7]=[CH:2][N:3]4[N:8]=3)[NH:22][CH:21]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N=c1ccccn1NC(=S)n1ccnc1
Reactant: ClCc1ncc(-c2ccccc2)[nH]1
Solvent: CN(C)C=O
Product: c1ccc(-c2c[nH]c(CSc3nc4ccccn4n3)n2)cc1
Temperature: 100 °C

Procedure:
A solution of imidazole-1-carbothioic acid (2-imino-2H-pyridin-1-yl)-amide (18 mg, 0.080 mmol) in DMF (0.5 mL) was added to 2-chloromethyl-5-phenyl-1H-imidazole (23 mg, 0.12 mmol) and the mixture was heated at 100° C. overnight. Volatiles were evaporated and the residue was purified by preparative LC-MS to yield the title compound. LC-MS: m/z=308.2 (MH+), tR=0.67 min, method A.
Reaction SMILES: [ClH:1].O1CCOCC1.[NH2:8][N:9]1[O:21][C:20]2[C:19]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]=3[S:13][C:12]=2[N:11]=[C:10]1[S:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=2)[CH2:35][CH2:34]1>>[ClH:1].[ClH:1].[ClH:1].[NH2:8][N:9]1[O:21][C:20]2[C:19]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[S:13][C:12]=2[N:11]=[C:10]1[S:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=2)[CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3c2ON(N)C(SCCCN2CCN(c4ccc5ccccc5n4)CC2)=N3)C1
Agent: Cl
Solvent: C1COCCO1
Product: NN1Oc2c(sc3c2CCNC3)N=C1SCCCN1CCN(c2ccc3ccccc3n2)CC1
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To 6 ml of 4N-hydrochloric acid-dioxane solution, 100 mg of 3-amino-7-tert-butoxycarbonyl-2-[3-(4-quinolin-2-ylpiperazin-1-yl)propylthio]-3,4,5,6,7,8-hexahydro-4-oxa-9-thia-1,3,7-triaza-9H-fluorene as synthesized in Example 1-13 was added and stirred for 2.5 hours. Distilling the solvent off under reduced pressure, 105 mg (100%) of 3-amino-2-[3-(4-quinolin-2-ylpiperazin-1-yl)propylthio]-3,4,5,6,7,8-hexahydro-4-oxa-9-thia-1,3,7-triaza-9H-fluorene trihydrochloride was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][C:8]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:9]=1[C:10]([NH:12][C:13]1[C:14]([OH:21])=[N:15][C:16]([CH3:20])=[N:17][C:18]=1[OH:19])=O>C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:9]=1[C:10]1[O:19][C:18]2[N:17]=[C:16]([CH3:20])[NH:15][C:14](=[O:21])[C:13]=2[N:12]=1
Reactant: Cc1nc(O)c(NC(=O)c2cc(F)ccc2Cl)c(O)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc2oc(-c3cc(F)ccc3Cl)nc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
22.2 g of phosphorus pentachloride were added to a suspension of the product obtained in step (b) in 300 ml of dry chloroform. The reaction mixture was stirred at room temperature for 3 h. Then another 22.2 g of phosphorus pentachloride were added and the reaction mixture was stirred at 60° C. for 4 h. After cooling to room temperature, the precipitate was filtered off, washed with a little dichloromethane and dried to give 30.2 g of the crude title compound.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:12]=3[N:13]=2)[CH:17]=1
Reactant: NCc1ccccc1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3cccnc3)nc(NCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-3-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-benzylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:6]([NH2:8])[N:7]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([NH:8][C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[N:4][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[Cl:16])(=[O:19])[CH3:18]
Reactant: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(N)nnc1-c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
A solution of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (2 gm, 8 mM) and acetic anhydride (10 mls) in acetic acid (20 mls) was stirred and heated to reflux for 2 hours. The solution was then cooled and evaporated down in vacuo. The residue was treated with aqueous 0.880 ammonia (100 mls) and the resultant mixture was stirred for 2 hours. The solid was separated by filtration, dried then recrystallized from isopropanol to give 5-acetamido-3-amino-6-(2,3-dichlorophenyl)-1,2,4-triazine. Yield 1.0 gms (42%), m.p. 250°-252° (uncorrected).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)C)=[CH:4][CH:3]=1.BrCC(C1C=CC(Cl)=CC=1)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CC(C(=O)c1ccc(Cl)cc1)N1CCNCC1
Agent: O=C(CBr)c1ccc(Cl)cc1
Product: O=C(CN1CCNCC1)c1ccc(Cl)cc1

Procedure:
4′-Chloro-2-(piperazin-1-yl)acetophenone was prepared as for 4′-chloro-2-(piperazin-1-yl)propiophenone except that commercially available 2-bromo-4′-chloroacetophenone (Aldrich, 10,127-3) is used instead of 2-bromo-4′-chloropropiophenone.
Reaction SMILES: O[CH:2]1[C:10]2[CH:9]=[C:8]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][C:7]3=[CH:6][C:5]=2[C:4](=O)[N:3]1[CH:24]([CH3:26])[CH3:25].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:26][CH:24]([N:3]1[CH2:4][C:5]2[CH:6]=[C:7]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:8]3=[CH:9][C:10]=2[CH2:2]1)[CH3:25]
Reactant: CC(C)N1C(=O)c2cc3c(cc2C1O)CCN(C(=O)OC(C)(C)C)CC3
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N1Cc2cc3c(cc2C1)CCNCC3
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of 1,1-dimethylethyl 1-hydroxy-2-(1-methylethyl)-3-oxo-2,3,5,6,8,9-hexahydroazepino[4,5-f]isoindole-7(1H)-carboxylate (1.0 g) and triethylsilane (0.95 ml) in DCM (20 ml), at 0° C., TFA (10 ml) was added dropwise and the mixture stirred for 1 h. the mixture was neutralized with 2M aqueous Na2CO3 and washed with ether discarding the organic layer. Then the aqueous layer was made basic with NaOH and extracted with DCM. The organic solution was washed with brine, dried over Na2SO4 and concentrated to afford a pale yellow solid (0.6 g, 88% yield).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][C@@H:18]([OH:29])[C:19]2([S:26][CH2:27][CH3:28])[S:23][CH2:24][CH3:25])[C@H:15]2[C@@:6]1([F:32])[C@:7]1([CH3:31])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:30])[CH:9]=[CH:8]1)(=[O:3])[CH3:2].CS(C)=O.C(OC(=O)C)(=O)C.C(O)(=O)C>O>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][C:18](=[O:29])[C:19]2([S:23][CH2:24][CH3:25])[S:26][CH2:27][CH3:28])[C@H:15]2[C@@:6]1([F:32])[C@:7]1([CH3:31])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:30])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CCSC1(SCC)[C@H](O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: CCSC1(SCC)C(=O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
A solution of 11β-(acetyloxy)-17,17-bis-(ethylthio)-9-fluoro-16α-hydroxyandrosta-1,4-dien-3-one (100 mg, 0.207 mmole) in a mixture of dry dimethylsulfoxide (2.0 ml), acetic anhydride (0.7 ml) and acetic acid (0.1 ml) was left standing at room temperature for 18 hours. The mixture was then added to water and was extracted with chloroform. The chloroform solution was washed with water, dried (MgSO4) and evaporated to afford the title compound (94 mg) as a solid.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O[N:26]1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15]([NH2:26])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Reaction time: 5 h
Yield: 75 %

Procedure:
48.6 g (1.0 eq) Boc-D-Glu(OBzl)-OH was dissolved in tetrahydrofuran, 24.8 g (1.5 eq) HOSu and 44.5 g (1.5 eq) DCC were added sequentially. After stirring for 5 hours in ice bath, the reaction was warmed to r.t and stirred for another 20 hours. A large number of white precipitate (DCU) precipitated, the precipitate was filtered out and washed with little tetrahydrofuran. The filtrate was stirred in ice-salt bath, and anhydrous ammonia was introduced to the solution. After 15 minutes, a large number of white precipitate precipitated, and stirred the mixture for another 1.5 hours, no more white solid precipitated out, and the reaction was completed. The precipitate was filtered and washed with tetrahydrofuran, and yellow oil was obtained after removing the tetrahydrofuran filtrate under vacuum. The yellow oil was diluted with AcOEt; and the pH of the solution was adjusted to 7 with 2N HCl aqueous solution in ice bath, and the solution was allowed to stand for 30 minutes. The AcOEt layer was separated, and successively washed with diluted hydrochloric acid, saturated sodium bicarbonate and water. After that, the AcOEt layer was dried with MgSO4 overnight. The mixture was filtered and the filtrate was evaporated to dryness under vacuum, and the residue was recrystallized with ethyl acetate-cyclo hexane to yield 34.2 g target compound with the yield of 75%, m.p.=122˜123° C., [α]=−1.8° (C=9.8 mg/mL, DMF)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=[O:8].[K+].[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[O:19])[CH2:17]Br)=[CH:14][CH:13]=1.C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3>C(#N)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:17][C:16]([C:15]1[CH:20]=[CH:21][C:12]([Br:11])=[CH:13][CH:14]=1)=[O:19])=[O:8]
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: O=C([O-])CCCCCO
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Solvent: CC#N
Product: O=C(CCCCCO)OCC(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A mixture of 8.5 g. (50 mmoles) of potassium 6-hydroxycaproate, 13.9 g. (50 mmoles) of p-bromophenacyl bromide, 0.75 g. (2 mmoles) of dicyclohexyl-18 -crown-6 in 500 ml. of acetonitrile is refluxed with stirring for 1 hour and stirred at room temperature overnight. The mixture is filtered and the filtrate evaporated to dryness in vacuo. The residual solid is recrystallized from benzene-hexane mixture affording 14.1 g. of p-bromophenacyl 6-hydroxycarproate, m.p. 79°-81° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:16][S:17]([O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCc1cccs1
Reaction time: 0.33 h

Procedure:
2-(Thiophen-2-yl)ethanol (1.05 g) was dissolved in tetrahydrofuran (25 ml), triethylamine (1.63 ml) and methanesulfonyl chloride (725 μl) were added and the mixture was stirred for 20 min. Saturated aqueous sodium hydrogen carbonate (50 ml) was added to the reaction mixture, and the mixture was extracted with diisopropyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object product (1.62 g).