Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:34][C:35]1[N:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:36]=1[C:37]([OH:39])=O.[S:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[CH2:50][NH2:51]>CN(C=O)C.CC(=O)OCC.CCCCCC.CC(=O)OCC>[Cl:34][C:35]1[N:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:36]=1[C:37]([NH:51][CH2:50][C:46]1[S:45][CH:49]=[CH:48][CH:47]=1)=[O:39]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: NCc1cccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1ccc(C(=O)NCc2cccs2)c(Cl)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
2.67 g (7.0 mmol) of HATU and 4.0 ml (23.2 mmol) of DIPEA were added at 0° C. to a solution of 1.0 g (5.8 mmol) of 2-chloro-6-methyl-nicotinic acid in DMF (20 ml), and the mixture was stirred for 20 min at 0° C. At that temperature, 656 mg (5.8 mmol) of thiophen-2-ylmethylamine were added. Stirring was then carried out for 16 h at RT. The mixture was then diluted with EA and washed in succession with sat. aq. NaHCO3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 4:1) of the residue yielded 966 mg (3.6 mmol, 63%) of 2-chloro-6-methyl-N-(thiophen-2-ylmethyl)nicotinamide.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(=O)([O-])O.[Na+]>CC(C)=O.C(O)(C)C>[F:1][C:2]([F:12])([F:13])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1
Reactant: OC1CCC(CCC(F)(F)F)CC1
Agent: O=[Cr](=O)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Solvent: CC(C)O
Product: O=C1CCC(CCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
35.6 g of 4-(3,3,3-trifluoropropyl)cyclohexanol were dissolved in 600 ml of acetone and 37 ml of water and mixed with 69 ml of Jones reagent. The mixture was stirred at room temperature for 24 h, mixed with 9 ml of isopropanol and 24 g of sodium hydrogen carbonate, the precipitate was filtered off and the residue was taken up in saturated aqueous sodium chloride. The mixture was extracted with ether and the combined ether phases were washed with water, dried and concentrated. Chromatography over silica gel (petroleum ether/ethyl acetate=3:1) gave the title product as a colourless oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:10]=1)C1C=CC=CC=1.Cl>>[CH3:21][C:19]1[N:20]=[C:16]([NH:15][C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][N:12]=2)[S:17][CH:18]=1
Reactant: Cc1csc(Nc2cc(OCc3ccccc3)ccn2)n1
Agent: Cl
Product: Cc1csc(Nc2cc(O)ccn2)n1
Yield: 38.7 %

Procedure:
Following the method of Example 3, Step A, 4-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (prepared according to Example 17) (2.3 g, 7.73 mmol), and HCl (38.7 mL, 116 mmol) (3M HCl) were reacted to provide 2-(4-methylthiazol-2-ylamino)pyridin-4-ol (0.620 g, 38.7% yield) as white solid. 1H NMR (CDCl3) δ 7.38 (bs, 1H), 6.23 (m, 2H), 6.10 (bs, 1H), 2.28 (s, 3H). HPLC (5 to 95) Rt=1.82 min; Mass spectrum (esi) m/z=208 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH2:9])[CH:8]=1.Cl.[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=O)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH:9][CH2:36][C:35]2[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:40][CH:39]=2)[CH:8]=1
Reactant: COc1ccc(C2=Cc3ccc(OC)cc3CC2)c(N)c1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCC3)cc1)=C2
Yield: 18.7 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)phenylamine (341 mg) and 4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (990 mg) according to an analogous synthetic method to Example 110, the title compound (113 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:20]([OH:23])(=[O:22])=[O:21])[CH:5]=[C:6]2[C:11]=1[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:7]2.C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[N+:64]([C:67]1[CH:68]=[C:69]([S:73](Cl)(=[O:75])=[O:74])[CH:70]=[CH:71][CH:72]=1)([O-:66])=[O:65].[N+](C1C=CC=CC=1S(Cl)(=O)=O)([O-])=O>O>[N+:64]([C:67]1[CH:68]=[C:69]([S:73]([NH:1][C:2]2[CH:3]=[C:4]([S:20]([OH:23])(=[O:22])=[O:21])[CH:5]=[C:6]3[C:11]=2[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:7]3)(=[O:75])=[O:74])[CH:70]=[CH:71][CH:72]=1)([O-:66])=[O:65]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 21.9 of 8-amino-1,3,6-naphthalenetrisulfonic acid, trisodium salt and 11.4 g of anhydrous sodium carbonate in 280 ml of water is added 24.0 g of m-nitrobenzenesulfonyl chloride. The mixture is stirred at room temperature for 16 hours, then an additional 1.0 g of sodium carbonate and 2.0 g of m nitrobenzenesulfonyl chloride are added and stirring is continued for 3 hours longer. The mixture is evaporated and the residue is dissolved in 200 ml of water. A copious amount of absolute ethanol is added and the solid formed is collected and washed with ethanol and ether, then is dried to yield 26.1 g of 8-m-nitrobenzenesulfonamido-1,3,6-naphthalenetrisulfonic acid, trisodium salt.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[CH2:8].C(C1C=C(C=CC=1)C(Cl)=O)=C.[F:29][C:30]1[CH:31]=[C:32]([C:37](=[O:48])[CH:38]=[C:39]2[NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=3[NH:40]2)[CH:33]=[C:34]([F:36])[CH:35]=1.C(=O)(O)[O-].[Na+]>COCCOCCOC.O.CN(C=O)C.C(Cl)Cl>[F:29][C:30]1[CH:31]=[C:32]([C:37](=[O:48])[C:38](=[C:39]2[NH:40][C:41]3[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=3[NH:43]2)[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([CH:7]=[CH2:8])[CH:10]=2)=[O:14])[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: C=Cc1cccc(C(=O)O)c1
Reactant: O=C(C=C1Nc2ccccc2N1)c1cc(F)cc(F)c1
Agent: C=Cc1cccc(C(=O)Cl)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: COCCOCCOC
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 70 °C
Yield: 68.5 %

Procedure:
A 3.8 g portion of oxalic acid chloride was gradually added dropwise to 30 ml of methylene chloride solution containing 1.54 g of 3-vinylbenzoic acid and a catalytically effective amount of DMF and stirred at room temperature for about 2 hours, and then an appropriate amount of Tol was poured into the mixture and evaporation was carried out under a reduced pressure, thereby preparing 3-vinylbenzoic acid chloride. This was dissolved in a small amount of Diglyme and gradually added dropwise to 5 ml of Diglyme solution containing 0.82 g of 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)ethanone which had been separately prepare in advance and 1.4 ml of TEA, under heating at 70° C. After completion of the dropwise addition, this was risen to 100° C. and heated for about 25 minutes, mixed with 0.1 ml of purified water, and further risen to 175° C. and heated for about 25 minutes. This was mixed with sodium bicarbonate aqueous solution, extracted several times with ethyl acetate, dried with anhydrous magnesium sulfate and concentrated, and then the thus formed residue was purified by a silica gel column chromatography to obtain 0.83 g (Reference Example 2-1) (68%) of 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-vinylphenyl)propane-1,3-dione as a yellow foam compound from an ethyl acetate-hexane (1:3) eluate. FA: 403
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[CH:5]=O.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].NCCC(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[CH:5]=[C:24]1[S:20][C:21](=[O:26])[NH:22][C:23]1=[O:25]
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)c(Br)c1
Reactant: O=C1CSC(=O)N1
Agent: NCCC(=O)O
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC4(CC3)OCCO4)c(Br)c2)S1

Procedure:
The title compound was prepared from 3-bromo-4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde (which was obtained in Example 56), 2,4-thiazolidinedione and β-alanine according to the procedure of Example 33 as a yellow solid; mp 109–111° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.79 (t, J=5.1 Hz, 4H), 3.12 (m, 4H), 3.93 (s, 4H), 6.87 (d, J=8.7 Hz, 1H), 7.52–7.55 (m, 1H), 7.61 (s, 1H), 7.83–7.87 (m, 1H), 12.5 (s, 1H); MS (ES) m/z: 425.1 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[C:4]([F:25])[N:3]=1.[O:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1>>[F:25][C:4]1[CH:5]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:7]=[C:2]([C:28]2[CH:29]=[CH:30][O:26][CH:27]=2)[N:3]=1
Reactant: OB(O)c1ccoc1
Reactant: OC1CCCC(Nc2ccc3ncc(-c4cc(F)nc(Cl)c4)n3c2)C1
Product: OC1CCCC(Nc2ccc3ncc(-c4cc(F)nc(-c5ccoc5)c4)n3c2)C1

Procedure:
The title compound is prepared from (1SR,3RS)-3-[3-(2-Chloro-6-fluoro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol (Intermediate T) and 3-furyl boronic acid using a procedure analogous to that described in Example 2.3.
Reaction SMILES: CC([CH:5]1[CH2:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][C:24]([CH3:29])([CH3:28])[CH2:23]3)=[CH:14][CH:13]=2)(O)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.Cl>C(O)C>[CH3:28][C:24]1([CH3:29])[CH2:25][CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][O:18][C:15]2[CH:14]=[CH:13][C:12]([C:9]3[CH2:10][CH2:5][NH:6][CH2:7][CH:8]=3)=[CH:17][CH:16]=2)[CH2:23]1
Reactant: CC1(C)CCCN(CCCOc2ccc(C3(O)CCN(C(=O)[O-])C(C(C)(C)C)C3)cc2)C1
Agent: Cl
Solvent: CCO
Product: CC1(C)CCCN(CCCOc2ccc(C3=CCNCC3)cc2)C1
Temperature: 7.5 °C
Reaction time: 0.25 h
Yield: 29.4 %

Procedure:
A mixture of crude 1,1-dimethylethyl-4-(4-{[3-(3,3-dimethyl-1-piperidinyl)propyl]oxy}phenyl)-4-hydroxy-1-piperidinecarboxylate (100 g) in 95% ethanol (500 ml) is cooled to 5-10° C. and concentrated hydrogen chloride (300 ml) is added at 5-10° C. over about 45 min, then stirred for about 15 min. The mixture is then heated to reflux (about 80-85° C.) for about 6 h. The mixture is concentrated under vacuum at 50-60° C., then water (500 ml) is added. The mixture is then cooled to 5-10° C. and the pH adjusted to pH 10-12 with 2N sodium hydroxide solution at 5-10° C. The mixture is warmed to 25-35° C., and extracted with ethyl acetate (500 ml, then 2×200 ml). The combined ethyl acetate layers are washed with water (200 ml), then 10% aqueous sodium chloride solution (200 ml). The solvent is removed under vacuum and the product is purified by column chromatography (100-200 mesh silica gels) using a linear gradient of MeOH/DCM 0-70% to give the title compound (21.7 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16]O)[CH2:13][CH2:14][OH:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][C@H:12]2[CH2:13][CH2:14][OH:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(N[C@@H](CO)CCO)c1ccc(F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)cc1)N1C[C@H]1CCO
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of 4-fluoro-N-[(1R)-3-hydroxy-1-(hydroxymethyl)propyl]benzene-sulfonamide (1 equiv) from step 2 in THF (20 mL/g) was added azodicarboxylic acid dipiperidide (1 equiv) followed by tri-n-butylphosphine (1 equiv) dropwise over 30 min. The reaction was stirred for 30 min then filtered. The filtrate was washed with THF and H2O (5 mL/g), then added to the resulting solution and stirred for 1 h. NaCl was added to separate the aqueous and organic layers. The layers were cut and the organic layer washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was triturated in MTBE and filtered. The resulting solution was concentrated and triturated in EtOAc/Hex (1:1) and then filtered. The resulting solution was then concentrated and purified by column chromatography with EtOAc/Hex 25-75% to give the desired material (77%) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=2)=[O:9])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1.[C:18]([N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([Br:17])=[CH:6][C:7]=1[C:8]([C:10]1[N:11]=[C:12]([N:28]2[CH2:29][CH2:30][CH2:31][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]2)[CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: Nc1ncc(Br)cc1C(=O)c1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(C(=O)c3cc(Br)cnc3N)n2)CC1
Temperature: 95 °C
Yield: 36.7 %

Procedure:
A mixture of (2-amino-5-bromopyridin-3-yl)(6-bromopyridin-2-yl)methanone (6.0 g, 16.8 mmol), 1-Boc-homopiperazine (3.64 ml, 18.48 mmol) and K2CO3 (8.13 g, 58.8 mmol) in DMF (50 ml) was heated at 95° C. for 17 hours. Additional 1-Boc-homopiperazine (0.3 ml, 0.1 eq) was added and the mixture heated at 95° C. for a further 4 hours for reaction to go to completion. Reaction mixture was then allowed to cool to room temperature and solvent removed in vacuo. The resulting solid was slurried in EtOAc and filtered through a short pad of silica, washing through with EtOAc and the resulting filtrate was then concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica (5 to 25% EtOAc/Petrol) to give pure title compound as a yellow solid (2.94 g, 37%). 1H NMR (DMSO-d6) (quoted as a mixture of rotamers) 1.25 (9H, d), 1.91-1.77 (2H, m), 3.34 (2H, masked signal), 3.57-3.50 (2H, m), 3.65-3.62 (2H, m), 3.77-3.70 (2H, m), 6.95 (1H, dd), 7.12 (1H, dd), 7.75-7.69 (1H, m), 7.80 (2H, br s), 8.32 (1H, d), 8.60 (1H, dd). ES+ 477.98.
Reaction SMILES: CC([O-])(C)C.[K+].CC(O)(C)C.[CH2:12]([O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C:13]#[CH:14]>O>[CH:12]([O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[C:13]=[CH2:14]
Reactant: C#CCOc1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: C=C=COc1cccc2ccccc12
Yield: 43 %

Procedure:
Into a similar reaction vessel as used in the abovementioned reaction, were placed 1.532 parts of t-BuOK and 6.816 parts of t-BuOH and to this, a mixture of 10.000 parts of 1-propargyloxynaphthalene and 23.333 parts of t-BuOH was dropwise added. The content was reacted at 50° C. for 60 minutes and then deionized water was added to stop the reaction. t-BuOH layer and water layer were removed off by using an evaporator, and the residue was added with an aqueous NaOH solution, extracted with an ether and the ether layer was separated. The ether solvent was removed off and the residue was subjected to a column chromatography (silica gel 200 mesh) to obtain a purified 1-allenyloxy naphthalene as a colorless oily product.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.S(Cl)([Cl:13])=O>>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([Cl:13])=[O:10])[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Product: C[C@H]1CC[C@H](C(=O)Cl)CC1

Procedure:
Trans-4-methyl-cyclohexanecarbonyl chloride was prepared by heating to reflux trans-4-methyl-cyclohexanecarboxylic acid (5 g, 0.035 mmol) in thionylchloride (5.0 ml) for 2 h followed by purification of the corresponding acyl chloride under reduced pressure in a Kugel-Rhorr apparatus collecting the fraction distilling at 95° C. yielding 5.1 g of the desired material which was used in the next step without further purification. This acyl chloride (1.5 ml, aprox. 10 mmol) was dissolved along with 5-Bromo-3-isopropylamino-thiophene-2-carboxylic acid methyl ester (2 g, 7.12 mmol) in anhydrous dichloroethane (2 mL) and heated at 80° C. (closed vial) for 12 h. The solvents were evaporated, the resulting crude material was dissolved in methanol and left 30 min. at room temperature, concentrated and purified via flash chromatography on silica gel using a 5% EtOAc 95% hexanes mixture of eluents, in this manner 600 mg (21%) of 5-Bromo-3-[isopropyl-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester the was isolated. 1H NMR(CDCl3, 300 MHz): 6.78 (s, 1H), 4.93 (m, 1H), 3.69 (s, 3H), 2.00-1.20 (m, 8H), 1.14 (d, 3H), 0.93 (d, 3H), 0.81 (d, 3H), 0.72-0.70 (m, 2H).
Reaction SMILES: FC1C=CC=CC=1CC=O.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[CH:19][CH:20]([CH:26]([CH3:28])[CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22].FC1C=CC=CC=1C=CC(C(C)C)C(O)=O.[O:45]([C:52]1[CH:53]=C([CH:57]=[CH:58][CH:59]=1)CO)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[CH:19][CH:20]([CH:26]([CH3:27])[CH3:28])[C:21]([O:23][CH2:24][C:25]1[CH:57]=[CH:58][CH:59]=[C:52]([O:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:53]=1)=[O:22]
Reactant: CCOC(=O)C(C=Cc1ccccc1F)C(C)C
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: CC(C)C(C=Cc1ccccc1F)C(=O)O
Agent: O=CCc1ccccc1F
Product: CC(C)C(C=Cc1ccccc1F)C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
2-Fluorophenylacetaldehyde is converted into ethyl 4-(2-fluorophenyl)-2-isopropyl-3-butenoate and hydrolyzed to the acid using the procedure of Example 9. The acid, 4-(2-fluorophenyl)-2-isopropyl-3-butenoic acid, is reacted, via the acid chloride, with m-phenoxybenzyl alcohol to yield m-phenoxybenzyl 4-(2-fluorophenyl)-2-isopropyl-3-butenoate, MS m/e 404.3 (M+). 2-Fluorophenylacetaldehyde is prepared from o-fluoro-β-methoxystyrene via the dimethylacetal using the procedure of Winterfeldt, Berichte 96(12), 3349 (1963).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=2)=[C:15]2[N:16]=[C:17]([CH3:26])[N:18]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:19](=[O:20])[C:14]2=[N:13]1>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[C:27]([C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)=[C:15]2[N:16]=[C:17]([CH3:26])[N:18]([CH2:21][C:22]([F:25])([F:23])[F:24])[C:19](=[O:20])[C:14]2=[N:13]1
Reactant: COc1ccc(-c2c3nc(C)n(CC(F)(F)F)c(=O)c3nn2-c2ccccc2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nc2c(-c3ccc(O)cc3)n(-c3ccccc3Cl)nc2c(=O)n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 66.9 %

Procedure:
BBr3 (3 ml, 1 M solution in CH2Cl2) was added to a solution of 2-(2-chlorophenyl)-3-(4-methoxyphenyl)-5-methyl-6-(2,2,2-trifluoroethyl )-2,6-dihydropyrazolo[4,3-d]pyrimidin-7-one (4A-11, 545 mg, 1.21 mmol) in CH2Cl2 (20 ml) at room temperature. The reaction mixture was stirred for 2.5 h, quenched with MeOH (2 ml), and concentrated under vacuum. The residue was redissolved in MeOH (2 ml) and heated under reflux for 0.8 h, cooled to room temperature, and concentrated under vacuum. The residue was purified on a Chromatotron using 4 mm plates and 50% EtOAc/hexanes to give an impure mixture of the desired product (352 mg). A second purification on a Chromatotron using 1 mm plates and 50% EtOAc/hexanes yielded the desired product 6A-1 (55 mg) as an oil: MS (m/z) 435.4 (M+H)+; 1H NMR (400 MHz, CDCl3): δ 7.63-7.53 (m, 5H), 7.52-7.42 (m, 3H), 5.00-4.80 (br m, 2H), 2.66 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([NH:15][C@@H:16]([CH3:22])[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[O:14])=[CH:11][N:10](COCC[Si](C)(C)C)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C1OCCOCCOCCOCCOCCOC1.[F-].[Cs+]>C(#N)C>[CH3:21][N:19]([CH3:20])[C:17]([C@@H:16]([NH:15][C:13]([C:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:5]=2)[NH:10][CH:11]=1)=[O:14])[CH3:22])=[O:18]
Reactant: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C(=O)N(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: C[C@H](NC(=O)c1c[nH]c2ncc(C3CC3)nc12)C(=O)N(C)C
Temperature: 25 °C
Yield: 45.5 %

Procedure:
To a solution of (S)-2-cyclopropyl-N-(1-(dimethylamino)-1-oxopropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 0.35 mmol) in acetonitrile (15.8 mL) at room temperature was added 18-crown-6 (92 mg, 0.35 mmol) and cesium fluoride (528 mg, 3.48 mmol). The reaction mixture was heated to reflux temperature for 48 h then cooled to room temperature and filtered over a pad of celite. The filtrate was evaporated under vacuum and the crude residue was partitioned between EtOAc (25 mL) and water (25 mL). The organic extract was dried (Na2SO4) and evaporated under vacuum. The crude residue was purified by preparative TLC (CH2Cl2/MeOH/NH4OH, 90:9.5:0.5) to give 48 mg (48%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-dimethylcarbamoyl-ethyl)-amide as an off-white solid. MS: (M+H)+=302.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5]O.N1C=CC=CC=1.S(Cl)([Cl:23])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][Cl:23]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)c(OC)c1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CCl)c(OC)c1OC
Temperature: 0 °C

Procedure:
5 g (24.47 mmol) of 2,3,4-trimethoxybenzyl alcohol (Aldrich, Steinheim, FRG) are dissolved, under argon, in 13.9 ml of abs. methylene chloride, and this solution is treated with 0.278 ml of pyridine . 3.05 ml of thionyl chloride in 6.94 ml of abs. methylene chloride are added dropwise to this solution, while cooling slightly (ice/water), within the period of 20 ml. During this procedure, the internal temperature rises to approximately 18-23° C. The mixture is left to react subsequently for 45 min and the slightly yellow solution is then poured onto ice/water. After the phases have been separated, the organic phase is washed once each with 1N sulfuric acid and water. After drying over Na2SO4, and removing the solvent, the oily residue is distilled under HV (b.p.: 93-95° C./0.07 Torr), and the title compound is obtained. 1H-NMR (220 MHz, CDCl3): 7.05 (d, 1H); 6.65 (d, 1H); 4.61 (s, 2H); 3.97 (s, 3H); 3.85 (s, 3H). HPLC: tRet =8.1 min (gradient II).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][S:9]SC.CSC1C=CC(O)=CC=1>>[CH3:8][S:9][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7]
Reactant: CSSC
Reactant: Oc1ccccc1
Agent: CSc1ccc(O)cc1
Product: CSc1ccccc1O
Yield: 41 %

Procedure:
The reaction was again repeated using identical amounts of phenol and methyl disulfide and 2.8 g of the solid H ELZ-20 catalyst recovered from the first repetition. The mixture was heated for 4 hours at which time the temperature was 179° C. After work-up as before, GC analysis indicated the presence of phenol (5.7 g, 46% recovered), ortho-(methylthio)phenol (5.1 g, 41% yield), para-(methylthio)phenol (2.7 g), and di-(methylthio)phenols (2.4 g).