Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:17]=3)=[CH:14][CH:15]=2)[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[N:7]=1)=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1.C1(C)C=CC=CC=1.C1C=CC=CC=1>CCOCC>[CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:17]=3)=[CH:14][CH:15]=2)[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[N:7]=1)=[S:42])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCNC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCNC(=S)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Yield: 37.7 %

Procedure:
To a dry, N2 purged 50 mL round bottom flask attached with condenser was added 1-(2-Chloro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1H-pyrazole-3-carboxylic acid ethylamide (100 mg, 206 μmol), Lawesson's reagent (200 mg, 494 μmol), and anhydrous toluene (8 mL). The reaction solution was allowed to stir at reflux for 14 hrs. The reaction solution was allowed to cool to room temperature prior to addition of a 1:1 mixture of benzene and Et2O. The resulting precipitate was removed by vacuum filtration through a Buchner funnel. The filtrate was concentrated on the Rotavapor and the crude residue was chromatographed through a 12 g SiO2 column using a mobile phase gradient of 100% Hx to 50% EtOAc to afford 39 mg (38% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.68 (br s, 1H), 8.02 (s, 1H), 7.83 (d, 1H), 7.72 (d, 1H), 7.48-7.70 (m, 5H), 7.42 (s, 1H), 7.22 (d, 1H), 6.83 (d, 1H), 3.87 (m, 2H), 3.07 (s, 3H), 1.36 (t, 3H). MS (ES) 502.3, 504.3 [M+H]+.
Reaction SMILES: C([C@H]([C@@H](C(O)=O)O)O)(O)=O.[NH2:11][C@@H:12]([C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][N:27]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH3:14].CN(C)C=O.C(N(CC)CC)C.[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([O:80][CH3:81])=[C:45]([CH:79]=1)[CH2:46][C@H:47]1[C:53](=[O:54])[N:52]([C:55](OC2C=CC=CC=2Cl)=[O:56])[CH2:51][C:50](=[O:65])[N:49]([CH2:66][C:67]2[C:72]([O:73][CH3:74])=[CH:71][C:70]([O:75][CH3:76])=[CH:69][C:68]=2[O:77][CH3:78])[CH2:48]1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([O:80][CH3:81])=[C:45]([CH:79]=1)[CH2:46][C@H:47]1[C:53](=[O:54])[N:52]([C:55]([NH:11][C@@H:12]([C:15]2[CH:16]=[C:17]([CH:25]=[CH:26][N:27]=2)[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:13][CH3:14])=[O:56])[CH2:51][C:50](=[O:65])[N:49]([CH2:66][C:67]2[C:68]([O:77][CH3:78])=[CH:69][C:70]([O:75][CH3:76])=[CH:71][C:72]=2[O:73][CH3:74])[CH2:48]1
Reactant: CC[C@@H](N)c1cc(C(=O)OC(C)(C)C)ccn1
Reactant: COc1cc(OC)c(CN2C[C@@H](Cc3cc(Cl)ccc3OC)C(=O)N(C(=O)Oc3ccccc3Cl)CC2=O)c(OC)c1
Agent: CN(C)c1ccncc1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)N1CC(=O)N(Cc2c(OC)cc(OC)cc2OC)C[C@@H](Cc2cc(Cl)ccc2OC)C1=O)c1cc(C(=O)OC(C)(C)C)ccn1
Reaction time: 0.08 h
Yield: 71.5 %

Procedure:
To the compound 5105 described in WO 06-059801A, that is, tert-butyl 2-[(1R)-1-aminopropyl]-isonicotinate D-tartrate (157 mg) in an N,N-dimethylformamide (1.5 ml) solution, triethylamine (0.113 ml) was added under ice cooling, and the mixture was stirred at that temperature for 5 minutes. To the reaction solution, the compound S141C described in WO 06-059801A, that is, (6R)-2-chlorophenyl 6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepane-1-carboxylate (250 mg) and 4-dimethylaminopyridine (49 mg) were added, and the mixture was stirred at 0° C. for 18 hours. The reaction solution was diluted with ethyl acetate, then was successively washed with saturated aqueous ammonium chloride solution and brine. The organic layer was dried over anhydrous sodium sulfate, then was concentrated. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate=1/1 to 1/2) to obtain tert-butyl 2-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-yl]carbonyl}amino)propyl]isonicotinate (compound S39a) (210 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.N1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]([O:19][C:20](=O)[CH3:21])(=O)[CH3:17].[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24]>C(OC(C)COC)(=O)C>[CH:11]1([CH2:17][CH2:16][O:19][CH:20]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=2)[CH3:21])[CH2:23][CH2:15][CH2:14][CH2:13][CH2:12]1.[C:23]([O:26][C:27]1[CH:3]=[CH:4][C:5]([CH:6]=[CH2:7])=[CH:8][CH:28]=1)(=[O:25])[CH3:24].[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Agent: C=Cc1ccc(O)cc1
Solvent: COCC(C)OC(C)=O
Product: C=Cc1ccc(OC(C)=O)cc1
Product: C=Cc1ccc(OC(C)OCCC2CCCCC2)cc1
Temperature: 20 °C

Procedure:
p-Hydroxystyrene (70 g) (VP-8000, manufactured by Nippon Soda Co., Ltd.) was dissolved in 320 g of propylene glycol monomethyl ether acetate (PGMEA) by heating, after dehydration by distillation under reduced pressure, the solution was cooled to 20° C. To the solution were added 0.35 g of pyridinium p-toluenesulfonate and 22.4 g of cyclohexane ethanol. t-Butyl vinyl ether (17.5 g) was gradually added to the solution to perform reaction at 20° C. for 5 hours. To the reaction solution were added 5.53 g of pyridine, and then 5.9 g of acetic anhydride was gradually added. The solution was subjected to reaction at room temperature for 1 hour. Ethyl acetate (320 ml) was added to the solution, and the reaction solution was washed with 150 ml of distilled water three times. The solvent was distilled off and the solution was concentrated. The thus-obtained oil was dissolved in 100 ml of acetone, and the solution was gradually poured into 2 liters of distilled water. The precipitated powder was filtered and dried, thereby 58 g of resin A-38 was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C[Si]([C:36]#[CH:37])(C)C>CN(C=O)C.C(N(CC)CC)C.CCOCC.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.[Cu]I>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:36]#[CH:37])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1cc(C)c(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 0.277 g (0.50 mmol) of the product of Example 11 in 2.0 mL of DMF and 2.0 mL of triethylamine was added 0.39 mL (0.2.748 mmol) of trimetylsilyl acetylene, 19 mg (0.027 mmol) of bis(triphenylphosphine)palladium(II)dichloride and 2.6 mg of copper(I)iodide. The reaction mixture was then heated to 65 degrees for 2 h and then cooled to room temperature and diluted with ether. The organics were washed with 5% Hcl solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 5 mL of THF, 1 mL of 1M tetrbutylammonium fluoride-THF solution was added and the reaction was stirred at room temperatue for 1 h, then diluted with ether, washed with 5% HCl solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica eluting with EtOAc-Hex (1:10) to provide 0.197 g (80%) of the desired product as a white foam. Electrospray Mass Spec: 450.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=1)=[O:9].C(O)(=O)C.OO.O>C(OO)(=O)C>[CH2:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8]2[O:9][N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=23)=[CH:15][CH:14]=1)[CH3:17]
Reactant: CCc1ccc(C(=O)c2ccccc2N)cc1
Agent: CC(=O)OO
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: CCc1ccc(-c2onc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 55 %

Procedure:
(2-Aminophenyl) (4-ethylphenyl)methanone, 60 g, (0.27 mole) was dissolved in 700 ml of 3% peracetic acid (prepared by warming a mixture of 500 ml of glacial acetic acid and 200 ml of 30% hydrogen peroxide on a steam bath for 1/2 hr, followed by cooling to 25° C.). The solution was allowed to stand for 60 hr, then poured into two liters of water. The mixture was extracted with methylene chloride and the organic extracts were diluted with ethyl acetate and extracted with dilute sodium hydroxide. The organic phase was then concentrated and the residue was chromatographed on silica gel, eluting with benzene. The product-containing benzene fractions were concentrated and the residue was distilled. The fraction boiling at 131° C./0.02 mmHg was collected and recrystallized from isopropanol to give 33.2 g (55%) of pale yellow crystals, m.p. 42.0°-42.5° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[Br:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]Br.C(N(CC)CC)C.O>CN(C=O)C>[Br:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: BrCCOCCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OCCOCCBr
Temperature: 45 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of N-hydroxyphthalimide (352 mg, 2.16 mmol) in 4 mL of DMF was added 2-bromoethyl ether (500 mg, 2.16 mmol) followed by triethylamine (218 mg, 2.16 mmol), and the resulting solution was stirred at 45° C. overnight. Water was added to quench the reaction, the aqueous layer was extracted with ethyl acetate for 3 times, the combined organic layers were washed with brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure, the crude product was purified by silica gel column chromatography (hexanes: ethyl acetate 2:1) to afford 2-(2-(2-bromoethoxy)ethoxy)isoindoline-1,3-dione (550 mg, 1.75 mmol, 81%) as colorless oil. 1H NMR (CDCl3, 500 MHz) δ (ppm): 3.38 (t, J=6.2 Hz, 2H), 3.81 (t, J=6.2 Hz, 2H), 3.87 (t, J=4.1 Hz, 2H), 4.37 (t, J=4.1 Hz, 2H), 7.73 (dd, J=3.0, 5.0 Hz, 2H), 7.82 (dd, J=3.2, 5.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[S:13][CH2:12][CH2:11][CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:19](Cl)(=[O:21])[CH3:20]>C1COCC1>[C:19]([C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[S:9][CH2:10][CH2:11][CH2:12][S:13]1)(=[O:21])[CH3:20]
Reactant: Clc1cccc(C2SCCCS2)c1
Reactant: CC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)C1(c2cccc(Cl)c2)SCCCS1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The crude 2-(3-chlorophenyl)-1,3-dithiane is dissolved in anhydrous THF (400 mL). After chilling to −78° C., a solution of n-butyl lithium (2.5 Molar, 42 mL) is added slowly by syringe. The solution is stirred for 30 minutes at −78° C., followed by the addition of acetyl chloride. The mixture is warmed to room temperature, quenched by the addition of a saturated aqueous solution of NH4Cl, washed with water, brine, and dried (Na2SO4). After removing the dessicant, the filtrate was concentrated in vacuo to provide the desired product.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C:11](=[CH:12][C:13](=[O:22])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[OH:23][CH2:24][C@@:25]12[C@@H:42]3[C@H:33]([C@H:34]4[C@@:38]([CH2:40][CH2:41]3)([CH3:39])[C:37](=[O:43])[CH2:36][CH2:35]4)[CH2:32][CH2:31][C:30]1=[CH:29][C:28](=[O:44])[CH2:27][C@@H:26]2[CH3:45].O[C@H:47]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(=CC(=O)CC1)C[C@H]3C>>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C:11](=[C:12]([CH3:24])[C:13](=[O:22])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[OH:23][CH2:24][C@@:25]12[C@@H:42]3[C@H:33]([C@H:34]4[C@@:38]([CH2:40][CH2:41]3)([CH3:39])[C:37](=[O:43])[CH2:36][CH2:35]4)[CH2:32][CH2:31][C:30]1=[C:29]([CH3:47])[C:28](=[O:44])[CH2:27][C@@H:26]2[CH3:45]
Reactant: C[C@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Reactant: C[C@@H]1CC2=CC(=O)CC[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Product: CC1=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(CO)[C@@H](C)CC1=O
Product: CC1=C2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)CC[C@@H]34)[C@@]2(CO)CCC1=O

Procedure:
Following essentially the same procedure and substituting 17β,19-dihydroxy-4-androsten-3-one, 19-hydroxy-1α-methyl-4-androstene-3,17-dione and 17β,19-dihydroxy-7α-methyl-4-androstene-3-one for the 17β,19-dihydroxy-6α,17α-dimethyl-4-androsten-3-one above results in the preparation of 17β,19-dihydroxy-4-methyl-4-androsten-3-one, 19-hydroxy-1α,4-dimethyl-4-androstene-3,17-dione, and 17β,19-dihydroxy-4,7α-methyl-4-androsten-3-one, respectively.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:9][C:8]([C:18]([F:21])([F:20])[F:19])=[C:7]([C:22]([F:25])([F:24])[F:23])[N:6]=1)=[O:4].[OH-].[Na+]>CO>[CH3:16][C:15]1[N:11]([C:10]2[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([C:22]([F:25])([F:23])[F:24])=[C:8]([C:18]([F:19])([F:20])[F:21])[CH:9]=2)[C:12]([CH3:17])=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)cc1-n1c(C)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C)n1-c1cc(C(F)(F)F)c(C(F)(F)F)nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution 3-(2,5-dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (1.28 g, 3.49 mmol) in methanol (25 ml) was added 1M NaOH (7 ml, 6.99 mmol) and the reaction mixture was left to stir at RT for 30 min. The solvent was removed in vacuo and water (20 ml) was added to the remaining residue. The pH was adjusted to pH 4/5 by the addition of 1M HCl. The mixture was extracted with EtOAc (3×20 ml) and the combined organic extracts were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo and dried in a vacuum oven (50° C.) overnight to give the crude title product as an orange solid which was used without further purification; LC-MS: Rt 1.23 min; MS m/z 353.1 [M+H]+; Method 2minLC_v003.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl.[CH2:13](N(CC)CC)C>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1ccc(O)cc1
Temperature: 25 °C

Procedure:
4-Hydroxyphenylacetic acid (1.75 g) was dissolved in methanol (30 ml) and 10M aqueous hydrochloric acid (0.15 ml) was added and heated to reflux for 15 hours. After cooling to room temperature, triethylamine (1 ml) was added, the mixture concentrated, purified by flash chromatography using silica gel (30 g) and eluted with ethyl acetate-hexane (2:8 volume by volume) to give Methyl 4-Hydroxyphenylacetate (4) (1.693 g). This was confirmed by spectroscopy--1H NMR (CDCl3) δ 3.58 (s, 2 H), 3.73 (s, 3 H), 6.75 (d, 2 H), 7.10 (d, 2 H).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][CH:22]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH2:20]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].C1(OC)C=CC=CC=1>C(Cl)Cl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[N:1]1([C:10]2[N:18]=[C:17]([N:19]3[CH2:20][CH2:21][CH:22]([NH2:25])[CH2:23][CH2:24]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nc(-n3cnc4ccccc43)c3nc[nH]c3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NC1CCN(c2nc(-n3cnc4ccccc43)c3nc[nH]c3n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
100 mg of product obtained in Example 22 are mixed with 3 ml of methylene chloride and 1.5 ml of trifluoroacetic acid containing 10% of anisole. The mixture is stirred at ambient temperature for 5 hours. It is concentrated to dryness and co-evaporation with toluene and then with methylene chloride is carried out. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. 128 mg of expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([N:8]([CH:10]2[CH2:12][CH2:11]2)[CH3:9])[CH:7]=1.C(OCC)(=O)C>CO.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH:10]2[CH2:11][CH2:12]2)[CH3:9])[C:5]([NH2:13])=[CH:4][C:3]=1[F:16]
Reactant: CN(c1cc(Cl)c(F)cc1[N+](=O)[O-])C1CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(c1cc(Cl)c(F)cc1N)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.8 %

Procedure:
To a solution of 400 mg (16.35 mmol) (5-chloro-4-fluoro-2-nitro-phenyl)-cyclopropyl-methyl-amine in 4 mL methanol was added 40 mg 10% palladium on activated charcoal (Fluka). The reaction mixture was stirred at room temperature under a hydrogen atmosphere of 1.7 bar for two hours. Ethyl acetate (10 mL) was added and the reaction mixture was filtered over Dicalite® speed plus (Acros) and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40) to give 240 mg (68%) of the title compound as a brown liquid. MS (ESI): m/z=215.075 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]([O:21][S:22]([CH3:25])(=[O:23])=[O:24])=[CH:19][N:20]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(OS(C)(=O)=O)cn2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: CS(=O)(=O)Oc1cnc(NC2CCNCC2)nc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of 4-(5-methanesulfonyloxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.85 g, 2.3 mmol, 1.0 equiv) in ethanol (15 mL) was added 4 M HCl in dioxane (2.85 mL, 11.4 mmol, 5.0 equiv) and the mixture was warmed up to 50° C. After 16 h, the reaction mixture was cooled down to rt, then poured into ice water and the pH was adjusted to 9-10 by addition of a sat. solution of potassium carbonate. Then, this solution was extracted three times with dichloromethane/isopropanol (4:1). The combined organic layers were concentrated by evaporation under reduced pressure to yield 0.62 g (99%) of the title compound as a colorless solid. MS (ISP): 273.0 [M+H]+.
Reaction SMILES: C([Li])CCC.[Si:6]([O:13][CH2:14][C:15]([C:18]1[CH:19]=[CH:20][C:21]([F:24])=[N:22][CH:23]=1)([CH3:17])[CH3:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1COCC1>[Si:6]([O:13][CH2:14][C:15]([C:18]1[CH:19]=[C:20]([B:25]([OH:30])[OH:26])[C:21]([F:24])=[N:22][CH:23]=1)([CH3:17])[CH3:16])([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:8])[CH3:7]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(F)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1cnc(F)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 107.7 %

Procedure:
n-Butyllithium (1.66 M in hexane) (Aldrich, St. Louis, Mo.; 0.429 mL, 0.712 mmol) was added (dropwise over 1 min) to a solution of 5-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-fluoropyridine (183.5 mg, 0.647 mmol) in THF (3.3 mL) at −78° C., and the resulting yellow solution was stirred at −78° C. for 1 h. Tri-isopropyl borate (Aldrich, St. Louis, Mo.; 0.179 mL, 0.777 mmol) was then added, and the resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was subsequently partitioned between EtOAc (50 mL) and water (30 mL) (1N HCl (about 200 μL) was added to bring the pH of the aqueous layer to 6.5). The organic layer was separated, and the aqueous layer was extracted with EtOAc (30 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 5-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-fluoropyridin-3-ylboronic acid (228.0 mg, 0.697 mmol, 108% yield) as a colorless oil. m/z (ESI, +ve) 328.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[C:4]=2[N:5]=[C:6]([S:8]([CH3:9])=[O:31])[N:7]=1
Reactant: CSc1nc(Cl)c2ccc(=O)n(-c3ccc(F)cc3F)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3ccc(F)cc3F)c2n1
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a solution of 4-chloro-8-(2,4-difluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (2.5 g, 7.6 mmol) in DCM (100 ml) was added m-CPBA (2.2 g, 10.2 mmol). The mixture was stirred for 10 min and evaporated. Flash chromatography (EtOAc) provided the title compound as a yellow solid (2.1 g, 80%): LC-MS m/z 356 (M+H)+ retention 2.43 min.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16]CC)=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[OH-].[Na+].C(O)C.Cl>O>[C:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[N:6][N:5]([CH2:4][C:3]3[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=3[Cl:1])[C:9]=2[CH:10]=1)([OH:16])=[O:15]
Reactant: CCOC(=O)c1ccc2nnn(Cc3ccc(Cl)cc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2nnn(Cc3ccc(Cl)cc3Cl)c2c1
Yield: 90.6 %

Procedure:
1-(2,4-dichlorobenzyl)-6-(ethoxycarbonyl)benzotriazole (0.60 g) was refluxed under heating in a mixed solvent of 5% aqueous solution of sodium hydroxide (6 g) and ethanol (20 g) for 0.5 hr. After cooling, concentrated hydrochloric acid (4 ml) and water (10 ml) were added to the reaction mixture, and the mixture was extracted with ethyl acetate, concentrated and dried to give the objective compound (0.50 g) as a crude product.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[K+].[C:19](=[S:21])=[S:20].[C:22]1([CH2:27]Cl)[S:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[C:22]1([CH2:27][S:20][C:19]([N:2]2[C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[S:21])[S:26][CH:25]=[CH:24][CH:23]=1
Reactant: S=C=S
Reactant: ClCc1cccs1
Reactant: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1cccs1

Procedure:
In the same manner as descsribed in Example 32, (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (4.33 g), KOH (2.33 g), carbon disulfide (1.22 ml), 50% ethanol (80 ml) and 2-thenyl chloride (3.1 g) are reacted and treated to give the title compound (3.15 g) as pale yellow powder.