Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:14]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
2.0 g of 4-chloro-3-nitrophenol was dissolved in 15 ml of N,N-dimethylformamide. Thereto was added 490 mg of sodium hydride (purity: 60%) in 10 minutes at 5°-10° C. Then, 1.53 g of benzyl chloride was added dropwise in 10 minutes. Stirring was conducted for 1 hour at 70° C. The reaction mixture was introduced into a mixture of 50 ml of ice water and 50 ml of ethyl acetate. The resulting organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was washed with n-hexane and then mixed with a mixture of diisopropyl ether and n-hexane. The resulting crystal was collected by filtration to obtain 1.8 g (yield: 59.4%) of 4-benzyloxy-2-nitro-chlorobenzene having a melting point of 50°-50.5° C.
Reaction SMILES: [CH2:1]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]([OH:26])[CH3:25])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:27]([O:30][CH:31]([CH3:35])[C:32](O)=[O:33])[CH2:28][CH3:29]>>[CH2:1]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([O:26][C:32](=[O:33])[CH:31]([O:30][CH2:27][CH2:28][CH3:29])[CH3:35])[CH3:25])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccc(-c2ccc(OC[C@H](C)O)cc2)nc1
Reactant: CCCOC(C)C(=O)O
Product: CCCCCCCCCc1ccc(-c2ccc(OCC(C)OC(=O)C(C)OCCC)cc2)nc1

Procedure:
(S)-5-nonyl-2-(4'-(2"-hydroxypropoxy)phenyl)pyridine (m.p. 77.6°-80.3° C.) was reacted with 2-propoxypropionic acid prepared in Example 3 in the same manner as in Example 3 to obtain 5-nonyl-2-(4'-(2"-(2"'-propoxypropionyloxy)-propoxy)phenyl)pyridine (m.p. 58.0° C.).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[O:13])[CH2:7]1)(=[O:4])=[O:3].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][S:2]([NH:5][CH:6]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[NH:16][CH:15]=2)=[O:13])[CH2:7]1)(=[O:4])=[O:3]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCC(NS(C)(=O)=O)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4CCC(NS(C)(=O)=O)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-methanesulfonylamino-cyclopentyl)-amide (109 mg, 0.176 mmol) was dissolved in dichloromethane (0.9 ml) and trifluoroacetic acid (0.54 ml, 7.0 mmol) was added. The orange solution was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.9 ml) and ethylenediamine (0.7 ml, 10.5 mmol) was added. The yellow solution was stirred at room temperature for 1.5 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 76 mg (88%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-methanesulfonylamino-cyclopentyl)-amide as an off-white powder. MS: (M+H)+=488; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.30 (br. s, 1H), 9.11 (s, 1H), 8.42-8.52 (m, 2H), 8.17 (d, J=7.2 Hz, 1H), 8.02 (s, 1H), 7.41 (dd, J=8.7, 1.5 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 4.27-4.40 (m, 1H), 4.18 (s, 3H), 3.67-3.82 (m, 1H), 2.92 (s, 3H), 2.53-2.63 (m, 1H), 1.97-2.20 (m, 2H), 1.65-1.81 (m, 2H), 1.55 (dt, J=12.3, 9.0 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>O1CCCC1>[CH:10]1([NH:6][C:5]2[CH:7]=[CH:8][C:2]([I:1])=[CH:3][C:4]=2[CH3:9])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CCCC1
Reactant: Cc1cc(I)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(I)ccc1NC1CCCC1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A mixture of 2.5 g (10.7 mmol) of 4-iodo-2-methylaniline, 1.0 ml (11.8 mmol) of cyclo-pentanone, 0.9 ml (16.1 mmol) of glacial acetic acid and 0.1 g of p-toluenesulphonic acid are stirred in 50 ml tetrahydrofuran for 30 minutes. Then 3.1 g (13.9 mmol) of sodium-triacetoxyborohydride are added and the mixture is stirred for a further 26 hours at ambient temperature. The solvent is distilled off and the residue is chromatographed on silica gel, eluting with petroleum ether/ethyl acetate 0 to 10%.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][NH2:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:20]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[C:24]=2[CH:23]=[CH:22][N:21]=1.C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][N:2]([CH2:10][CH2:11][NH:12][S:30]([C:25]1[C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:31])=[O:32])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(CCN)Cc1ccccc1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCNS(=O)(=O)c1cccc2cnccc12)Cc1ccccc1
Reaction time: 1 h
Yield: 82 %

Procedure:
In 70 ml of methylene chloride were dissolved 3.24 g of 2-(N-methyl-N-benzylamino)ethylamine and 2.0 g of triethylamine, and to the solution was added dropwise 50 ml of a methylene chloride solution containing 3.0 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the methylene chloride solution, the mixed solution was stirred at a temperature of 15° C. to 25° C. for one hour, and then the reaction solution was washed with water and extracted with a 10% aqueous hydrochloric acid solution. The aqueous layer was washed with chloroform, rendered alkaline with a 1N aqueous sodium hydroxide solution, extracted with chloroform, and then the chloroform layer was washed with water, dried with anhydrous magnesium sulfate and the chloroform was distilled therefrom under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (silica gel:100 g; solvent:chloroform) to give 3.84 g of N-[2-(N-methyl-N-benzylamino)ethyl]-5-isoquinolinesulfonamide, i.e., Compound (65) in a yield of 84%.
Reaction SMILES: [CH3:1][C:2]1[CH2:9][CH2:8][CH:7]=[C:6]([CH3:10])[CH2:5][CH2:4][CH:3]=1.CC1CCC(C)=CCCC=1.[BrH:21]>>[CH3:10][C:6]12[CH:3]([Br:21])[C:2]([CH3:1])([CH2:4][CH2:5]1)[CH2:9][CH2:8][CH2:7]2
Reactant: Br
Reactant: CC1=CCCC(C)=CCC1
Agent: CC1=CCCC=C(C)CC1
Product: CC12CCCC(C)(CC1)C2Br
Yield: 93.3 %

Procedure:
A mixture of 68 g (0.5 mol) 1,5-dimethyl-1,5-cyclooctadiene and 1,6-dimethyl-1,5-cyclooctadiene (ratio 80/20) was boiled under stirring for 1 hour with 500 ml 48% hydrogen bromide and 10 g of AMBERLYST A15 ion-exchange resin. Thereafter, the reaction product was subjected to azeotrope distillation with the aqueous hydrogen bromide solution. The distillate was then extracted with pentane. The pentane layer was treated as described in Example 1a. By fractional distillation under reduced pressure 81 g 1,5-dimethyl-8-bromobicyclo[3,2,1]octane (b.p. 93° C./10 mm Hg) was obtained in 93.3% yield. The purity of the product according to gas-liquid chromatography was more than 98%.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[N-:20]([C:23]#[N:24])[C:21]#[N:22].[Na+]>C(O)CCC>[C:21]([NH:20][C:23](=[NH:24])[NH:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:23]([NH:20][C:21]#[N:22])=[NH:24])#[N:22]
Reactant: N#C[N-]C#N
Reactant: CCCCCCCCCCCCNCCCN
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CCCCCCCCCCCCN(CCCNC(=N)NC#N)C(=N)NC#N

Procedure:
3-Dodecylaminopropylamine dihydrochloride (15 g.) sodium dicyanamide (9.47 g.) and butanol (250 ml.) were heated under reflux for 4 hours. The mixture was allowed to cool, and filtered, and the solvent was evaporated under reduced pressure. The residue was suspended in toluene and evaporated to small volume under reduced pressure to yield a pale oil, which was purified by chromatography on silica gel, using a gradient elution of isopropanol/methylene dichloride starting at 1:9, and then eluting the required product using a ratio of 1:4. The product 1-(3-cyano-guanidino)-3-(3-cyano-1-dodecylguanidino)propane was obtained as a solid m.p. 126°-129°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[NH2:27].Cl.[N:29]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:6]=1[NH:27][N:29]=[C:13]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: COc1cc(CS(=O)(=O)c2cccc3ccccc23)c(N)c(OCCCl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OCCCl)c2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 3 °C

Procedure:
A mixture of 2-(2-chloro-ethoxy)-4-methoxy-6-(naphthalene-1-sulfonylmethyl)-phenylamine (1.0 g, 2.46 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.17 g, 2.6 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.0 g, 2.39 mmoles).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:7]2[C:3]=1[C:4](=N)[NH:5][C:6]2=[NH:29].[ClH:31].[CH2:32]([NH:39][C:40]1[S:41][CH2:42][C:43](=[NH:45])[N:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N=C1C2C(=CC=CC=2)C(=N)N1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:31].[NH:29]=[C:6]1[C:7]2[C:3](=[C:2]([CH3:1])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:4](=[C:42]2[S:41][C:40]([NH:39][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:44][C:43]2=[NH:45])[NH:5]1
Reactant: N=C1CSC(NCc2ccccc2)=N1
Reactant: Cc1c2c(c(-c3ccccc3)c(-c3ccccc3)c1-c1ccccc1)C(=N)NC2=N
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Agent: N=C1NC(=N)c2ccccc21
Product: Cc1c2c(c(-c3ccccc3)c(-c3ccccc3)c1-c1ccccc1)C(=N)NC2=C1SC(NCc2ccccc2)=NC1=N

Procedure:
Using a procedure similar to that described in Example 9, part B above but substituting 4-methyl-5,6,7-triphenyl-1,3-diiminoisoindoline and 2-benzylamino-4-imino-2-thiazoline hydrochloride for the 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, there is obtained as the product 1-imino-4-methyl-5,6,7-triphenyl-3-(2-benzylamino-4-imino-2-thiazolin-5-ylidene)isoindoline hydrochloride.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]([NH:26][CH2:27][CH2:28][C@H:29]([N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42])[CH2:30][F:31])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:52]([O:55][C@@H:56]([CH3:60])[C:57](Cl)=[O:58])(=[O:54])[CH3:53]>ClCCl>[C:52]([O:55][C@H:56]([CH3:60])[C:57]([N:26]([C@@H:21]([C:9]1[N:10]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[S:12][C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:22]([CH3:24])([CH3:25])[CH3:23])[CH2:27][CH2:28][C@H:29]([N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42])[CH2:30][F:31])=[O:58])(=[O:54])[CH3:53]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CC(C)(C)C(NCC[C@@H](CF)N1C(=O)c2ccccc2C1=O)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)O[C@H](C)C(=O)N(CC[C@@H](CF)N1C(=O)c2ccccc2C1=O)[C@@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-((2S)-4-(1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)-1-fluorobutan-2-yl)isoindoline-1,3-dione (65 mg, 0.125 mmol) in dichloromethane (1 mL, 0.1 M solution) at room temperature was added DIEA (65.3 μL, 0.375 mmol). (S)-1-Chloro-1-oxopropan-2-yl acetate (35 μL, 0.276 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for 1.5 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and filtered. After the volatile organic materials were removed in vacuo, the crude diastereomers were purified by preparative reverse phase HPLC. The combined fractions of each diastereomer were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The nonpolar diastereomer, (R)-1-(((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)((S)-3-(1,3-dioxoisoindolin-2-yl)-4-fluorobutyl)amino)-1-oxopropan-2-yl acetate, was obtained in 23% (10 mg). LC/MS (uplc) MH+ 706.2, 1.37 min. The polar isomer, (R)-1-(((S)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)((S)-3-(1,3-dioxoisoindolin-2-yl)-4-fluorobutyl)amino)-1-oxopropan-2-yl acetate, was obtained in 12% (5 mg). LC/MS (uplc) MH+ 706.2, 1.36 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[O:9]=[C:10]1[NH:14][C@@H:13]([CH2:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[CH:19]3)[CH2:12][O:11]1>C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[C:16]([CH2:15][C@H:13]4[CH2:12][O:11][C:10](=[O:9])[NH:14]4)[CH:17]=3)[NH:21][CH:20]=2)[CH2:4][CH2:3]1
Reactant: O=C1N[C@@H](Cc2ccc3[nH]ccc3c2)CO1
Reactant: CN1CCC(=O)CC1
Solvent: CC(=O)O
Product: CN1CC=C(c2c[nH]c3ccc(C[C@H]4COC(=O)N4)cc23)CC1
Yield: 25.5 %

Procedure:
1-Methyl-4-piperidone (0.47 g, Aldrich) was added to a stirred solution of the product from step (b) (0.30 g) in glac. acetic acid (2.0 ml) and the mixture stirred at 100° C. for 2 hours. The cooled mixture was poured onto ice/NH4OH (20 ml) and the resulting solid filtered off. The latter was eluted through a silica column using DCM/EtOH/NH4OH (60:8:1) as eluant and crystallised from ethyl acetate to give the desired product as a colourless solid (0.11 g), mp 225°-227° C., [α]D20 -45.4° (c=0.5, 1N aqu. HCl). Elemental analysis and 1H NMR were consistent with the proposed structure.
Reaction SMILES: [Br:1][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:25].[C:26](OC(=O)C)(=[O:28])[CH3:27].O>N1C=CC=CC=1>[C:26]([O:25][C@@H:3]1[C@@H:2]([Br:1])[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]3[C@@]2(C)C[C@@H]1Br
Reaction time: 8 h

Procedure:
2β-Bromo-3α-hydroxy-5α-pregnane-11,20-dione (750 mg.) in pyridine (2 ml.) was treated with acetic anhydride (1 ml.) and the mixture was allowed to stand at room temperature overnight. It was then poured into water to give a white solid (720 mg.) which was recrystallised from methanol to give 3α-acetoxy-2β-bromo-5α-pregnane-11,20-dione (471 mg.) as white crystals, m.p. 154°-156°, [α]D + 128.5°.
Reaction SMILES: Cl[C:2]1[N:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.C(O)(=[O:29])C>>[CH3:19][C:17]1[N:18]=[C:14]([C:8]2[N:7]=[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([OH:29])[N:26]=[CH:25][C:5]=43)[CH:9]=2)[N:15]([CH2:20][C:21]([F:22])([F:23])[F:24])[N:16]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(CC(F)(F)F)n1
Reactant: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(CC(F)(F)F)n1

Procedure:
A solution of 8-chloro-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (4 g, 10.4 mmol) in acetic acid (100 mL) was heated to 150° C. for 65 hours. The reaction was cooled, concentrated in vacuo and loaded onto an Isolute SCX-2 cartridge, washing with methanol and eluting with 2M ammonia in methanol. Basic fractions were combined and concentrated in vacuo, the resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 2-[5-Methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol. LCMS: RT=2.25 min, [M+H]+=367.33. 1H NMR 300 MHz (DMSO-d): δ 8.40 (1 H, br, s), 7.94 (1 H, s), 5.85 (1 H, s), 5.77 (1 H, s), 5.73 (2 H, m), 4.56 (2 H, m), 4.49 (2 H, m), 2.29 (3 H, s)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=O)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17].C1COCC1>C(OCC)(=O)C>[CH2:14]([N:18]=[CH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[Cl:1])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN
Reactant: O=Cc1ccc2nccc(Cl)c2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN=Cc1ccc2nccc(Cl)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a suspension of 4-chloro-quinoline-6-carbaldehyde (3.59 g, 18.73 mmol) in heptanes (36 mL) was added n-butylamine(1.51 g, 20.60 mmol, 1.1 equiv.) at room temperature. The reaction mixture was stirred for 5 h at room temperature by this time all solids were dissolved and gave a light brown solution containing a little oily stuff on the wall of flask. Then, 4 mL of THF was added and the clear solution was stirred for another 15 h. This solution was diluted with ethyl acetate (50 mL) and washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solvents were removed under the vacuum and the remaining residue was dried under high vacuum to afford 4.62 g (˜100% yield) of butyl (4-chloro-quinolin-6-ylmethylene)-amine as a brown oil which was used directly for the next substitution reaction. LRMS(+) m/e calcd for C14H15ClN2 (M+H)+247.7, found 247.2.
Reaction SMILES: [CH3:1][C:2]([N:6]1[Si:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][Si:7]1([CH3:14])[CH3:13])([CH3:5])[C:3]#[CH:4].C([Li])CCC.[CH:20](=[O:22])[CH3:21].O>O1CCCC1>[OH:22][CH:20]([C:4]#[C:3][C:2]([N:6]1[Si:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][Si:10]1([CH3:11])[CH3:12])([CH3:1])[CH3:5])[CH3:21]
Reactant: CC=O
Reactant: C#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Temperature: -20 °C

Procedure:
1-(1,1-Dimethyl-2-propynyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (1.0 g) in dry tetrahydrofuran (10 ml) was cooled to −50° C. under an atmosphere of nitrogen with stirring and a solution of n-butyl lithium (2.0 ml, 2.5M solution in hexanes) was added dropwise over 2 minutes. The mixture was stirred for 0.25 hour at −50° C., allowed to warm to −20° C. then acetaldehyde (0.22 g) in tetrahydrofuran (2 ml) was added dropwise. The reaction was stirred at −20° C. for 1.5 hours, allowed to warm to ambient temperature over 1 hour and treated with water. The product was extracted with ethyl acetate (three times) and the extracts were combined, washed with water (twice) then dried over magnesium sulphate and evaporated under reduced pressure to give (2-hydroxy-5-methylhex-3-yn-5-yl)- 2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane,1.06 g, as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Br:10]Br>C(O)(=O)C>[Br:10][CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: BrBr
Reactant: CSc1nccc(C)n1
Solvent: CC(=O)O
Product: CSc1nccc(CBr)n1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 55.3 %

Procedure:
To a solution of 4-methyl-2-methylthiopyrimidine (12.6 g, 0.09 mol) in acetic acid (50.0 mL) was added bromine (5.5 mL, 0.11 mol) and heated at 80° C. under argon atmosphere for 2 h. Acetic acid was distilled in vacuo, the residue was triturated with dichloromethane (100.0 mL) and poured into satd. sod.bicarbonate solution (200.0 mL). Additional dichloromethane (100.0 ml) was added and stirred for 15 min. The organic phase was washed with water (3×100 mL), dried (Na2SO4), and concentrated under reduced pressure. The dark colored residue was purified by flash chromatography (EtOAc/hexane 1:4 v/v) to afford 4-(bromomethyl)-2-(methylthio)pyrimidine (10.9 g, 55%) as a dark colored liquid: 1H NMR (CDCl3/400 MHz) δ8.50 (d, 1H, J=4.8 Hz), 7.09 (d, 1H, J=4.8 Hz), 4.34 (s, 2H), and 2.56 (s, 3H); ESMS m/z 219 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=1[O:40][CH3:41]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=4[O:40][CH3:41])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCCC(=O)Cc1ccc(OCCCBr)c(OC)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCC(=O)Cc1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(OC)c1
Yield: 68.7 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (3 g), 1-[4-(3bromopropoxy)-3-methoxyphenyl]pentanone (3.7 g, 11.3 mmol) acetonitrile (140 ml) was heated at reflux for 4 hours. At the end of the reaction, the mixture was cooled and filtered. The filtrate was concentrated to an oil. Purification was performed by flash chromatography over a silica gel column (SiO. 55 g; eluted with 1% methanol in dichloromethane, 600 ml; 3% methanol: 97% dichloromethane, 400 ml). The fractions containing pure product were pooled and concentrated to a solid (4.3 g, 91%). Recrystallization from ethanol (10 ml) gave a powdery solid of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-pentanone (3.22 g), m.p.=79-80° C.