Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:12])[CH:3]=1.Br[CH2:14][CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:12][CH2:14][CH2:15][O:16][Si:17]([CH:21]([CH3:22])[CH3:23])([CH:18]([CH3:20])[CH3:19])[CH:24]([CH3:25])[CH3:26])[CH:3]=1
Reactant: CC(C)[Si](OCCBr)(C(C)C)C(C)C
Reactant: Oc1cc(Br)c2ccccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCOc1cc(Br)c2ccccc2c1)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
A stirred mixture of 4.38 g (19.6 mmol) of 1-bromo-naphtalen-3-ol (prepared according to the procedure of M. S. Newman, V. Sankaran, D. R. Olson, J. Am. Chem. Soc. 1976, 98, 3237–3242), 5.52 g (19.6 mmol) of 1-bromo-2-triisopropylsilyloxy-ethane, 13.56 g (98.1 mmol) of potassium carbonate and 1.45 g (3.9 mmol) of tetrabutylammonium iodide in 50 mL of dimethylformamide is heated to 60° C. for 4 hours. Then an additional 0.55 g (2.0 mmol) of 1-bromo-2-triisopropylsilyloxy-ethane are added and stirring is continued for another hour at 60° C., after which TLC analysis indicated complete consumption of 1-bromo-naphtalen-3-ol. The mixture is allowed to cool to room temperature and brine is added. The resulting solution is extracted with ethyl acetate. The organic solution is washed twice with brine and the combined aqueous layers are back extracted with ethyl acetate. The organic layers are combined, dried, filtered and concentrated under reduced pressure. The oily brown residue is purified by column chromatography on silica gel (97.5:2.5 n-hexane/diethylether) to afford above title compound as a brown solid.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:13]1([C:5]2([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[S:1](=[O:3])(=[O:2])[NH:4]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=S1(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc21

Procedure:
Various procedures have been reported for synthesizing 3-disubstituted-benz[d]isothiazole-1,1-dioxides and 3,3-disubstituted-2,3-dihydrobenz[d]isothiazole-1,1-dioxides from saccharin (3-oxo-2,3-dihydrobenz[d]isothiazole-1,1-dioxide) and from saccharin pseudo-chloride (3-chlorobenz[d]isothiazole-1,1-dioxide). As reported by A. Mustafa et al, J. Chem. Soc., 1952, p. 1339, the treatment of saccharin pseudo-chloride with excess phenylmagnesium bromide gave the corresponding 3,3-diphenyl-2,3-dihydrobenz[d]isothiazole-1,1-dioxide in almost quatitative yield. Methyl-, ethyl-, n-propyl- and n-butylmagnesium halides were reported by these authors to react analogously. R. A. Abramovitch et al, J. Chem. Soc., Perkin Trans I, 1974(22), p. 2589, reviewed and reinvestigated the reactions of saccharins with alkyl and aryl Grignard reagents and found that either the 3-alkyl (or 3-aryl)-benz[d]isothiazole-1,1-dioxide and/or the open-chain tertiary alcohol, o--CR2OH benzenesulfonamide wherein R is alkyl (or aryl) were obtained with one exception. When saccharin was treated with an excess of phenylmagnesium bromide in boiling tetrahydrofuran, 3,3-diphenyl-2,3-dihydrobenz[d]isothiazole-1,1-dioxide was obtained as the minor product together with the open-chain tertiary alcohol.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:29][CH2:30][OH:31].CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][OH:31])[CH2:23][CH2:24]1
Reactant: OCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(CCO)CC3)c2n1
Temperature: 50 °C
Reaction time: 7 h
Yield: 32.7 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine (for example, as prepared for Intermediate 34) (0.038 g, 0.10 mmol) in DMF (0.4 mL) was added to 2-bromoethanol (0.0085 mL, 0.12 mmol). DIPEA (0.040 mL, 0.23 mmol) was added and the reaction mixture heated at 50° C. for 18 hours. An additional aliquot of the 2-bromoethanol (commercially available, for example, from Aldrich) (0.015 mL) and DIPEA (0.040 mL, 0.23 mmol) were added and heating continued for a further 7 hours. The reaction mixture were stirred at room temperature for 72 hours then diluted with DMSO:MeOH (0.2 mL) and the resultant solution purified by MDAP (Method A). Appropriate fractions were combined and evaporated in vacuo. The residue was dissolved in 4M HCl in dioxane (0.2 mL) and allowed to stand at room temperature for 18 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The samples were dissolved in 1:1 MeOH:DMSO (0.6 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a TFA modifier. The solvent was evaporated in vacuo. The residue was redissolved in methanol (0.5 mL) and applied to top of 0.1 g aminopropyl SPE (preconditioned with methanol, 1.5 mL). The cartridge was washed with methanol (1.5 mL). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound (0.0133 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[N:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:25][C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Nc1ccncc1
Product: Cc1cc(Nc2cc3ccccc3c(Nc3ccncc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 273 was used, starting (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and pyridin-4-ylamine to give N3-(5-methyl-1H-pyrazol-3-yl)-N1-pyridin-4-yl-isoquinoline-1,3-diamine. LC-MS m/e 317(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH:7]1[NH:11][CH2:10][CH2:9][S:8]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1.OS(O)(=O)=O>[CH3:16][S:17]([N:11]1[CH2:10][CH2:9][S:8][CH:7]1[CH2:6][O:5][C:4]1[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=1[O:2][CH3:1])(=[O:19])=[O:18]
Reactant: COc1ccccc1OCC1NCCS1
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: COc1ccccc1OCC1SCCN1S(C)(=O)=O
Yield: 89.3 %

Procedure:
A solution of 2-(o-methoxyphenoxy)methyl-thiazolidine (1.83 g) in pyridine (6 ml) is treated with methane sulphonyl chloride (1.2 g) at room temperature. After 4 hours the mixture is diluted with 2N H2SO4, extracted with Et2O, to afford after the usual work-up 2.2 g of 3-methanesulphonyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p. 118°-120° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[NH:16][C:15](=S)[CH2:14][CH2:13][CH2:12][C:11]=3[CH:18]=2)[CH:2]=1.[F:19][C:20]([F:26])([F:25])[C:21]([NH:23][NH2:24])=O.C1(O)CCCCC1.FC(F)(F)C(O)=O>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[N:16]4[C:21]([C:20]([F:26])([F:25])[F:19])=[N:23][N:24]=[C:15]4[CH2:14][CH2:13][CH2:12][C:11]=3[CH:18]=2)[CH:2]=1
Reactant: NNC(=O)C(F)(F)F
Reactant: S=C1CCCc2cc(-c3cccnc3)ccc2N1
Solvent: O=C(O)C(F)(F)F
Solvent: OC1CCCCC1
Solvent: CS(C)=O
Product: FC(F)(F)c1nnc2n1-c1ccc(-c3cccnc3)cc1CCC2
Temperature: 120 °C

Procedure:
A flask containing the title compound from Example 2 Step E (9.0 mg, 0.04 mmol), 2,2,2-trifluoroacetohydrazide (3.2 mg, 0.04 mmol) and cyclohexanol (0.50 mL) was heated at 120° C. overnight. The reaction was then concentrated to give a residue that was diluted with dimethylsulfoxide, acidified with trifluoroacetic acid, and passed through a syringe filter before being purified by reverse phase HPLC (C18 column, 10 to 100% acetonitrile/water, both 0.1% v/v trifluoroacetic acid). Fractions containing product were combined, 1 M hydrochloric acid was added, and the solution concentrated to provide the title compound: LCMS m/z 330.99 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.09 (br s, 1H), 8.76 (br s, 1H), 8.26 (d, J=Hz, 1H), 7.75-7.59 (m, 4H), 3.34 (br s, 1H), 2.90-2.85 (m, 1H), 2.52-2.40 (m, 3H), 2.27 (br s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccncc1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Product: O=C(NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1)c1ccncc1

Procedure:
The N-[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-isonicotinamide was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and isonicotinic acid as described above in EXAMPLE 1, Step 2.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10]C1CC2C(=O)C(CSC2)C1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([O:8][C:9](=[O:21])[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CC2CSCC(C1)C2=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)OCc1ccccc1
Reaction time: 48 h
Yield: 40.6 %

Procedure:
To a solution of (9-oxo-3-thia-bicyclo[3.3.1]non-7-yl)-carbamic acid benzyl ester (16, 4.2 g, 13.7 mmol) in ethanol (172 ml) was added sodium borohydride (0.78 g, 20.6 mmol) portionwise at room temperature. The solution was stirred for 1 hour before addition of sodium borohydride (0.2 g, 5 mmol). The reaction mixture was stirred for 2 days, a further portion of sodium borohydride (0.340 g, 9 mmol) was added, and stirring was continued for 4 hours. The mixture was then concentrated under reduced pressure and cold water was added to the residue as well as dichloromethane. After a extraction of the aqueous phase with dichlormethane, the combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (cyclohexane:ethyl acetate 40:60) to yield 9-hydroxy-3-thia-bicyclo[3.3.1]non-7-yl)-carbamic acid benzyl ester as a white solid (0.84 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:29][C:30]1[N:35]=[CH:34][C:33]([CH2:36]OS(C)(=O)=O)=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:36][C:33]2[CH:34]=[N:35][C:30]([Cl:29])=[CH:31][CH:32]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CS(=O)(=O)OCc1ccc(Cl)nc1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(Cc3ccc(Cl)nc3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with methanesulfonic acid 6-chloro-pyridin-3-ylmethyl ester (described in Journal of Organic Chemistry (1999), 64(23), 8576-8581) gave the title compound.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]=3[C:30]([F:33])([F:32])[F:31])[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].CO.[Li+].[OH-]>C1COCC1>[OH:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]=3[C:30]([F:31])([F:32])[F:33])[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 73.4 %

Procedure:
(R/S)-Ethyl 2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetate (150 mg, 0.327 mmol) was dissolved in THF (2 mL) at 0° C. and MeOH (0.5 mL) and 1N LiOH (0.327 mL, 0.327 mmol) were added. After stirring for 1 h, the solution was concentrated and then EtOAc was added. The EtOAc was washed with 1 N HCl aqueous. The organic layer was dried (MgSO4), filtered and concentrated to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid Int-V (110 mg, 0.240 mmol, 73.4% yield): LCMS=431.9[M+H]+, 1H NMR (400 MHz, methanol-d4) δ ppm 8.19 (2 H, d, J=8.79 Hz), 7.51-7.79 (7 H, m), 5.26 (1 H, s).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:16]C)=[N:5][C:6]([CH3:15])=[C:7]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[N:10]=2)[CH:8]=1)[CH3:2].[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[CH2:1]([C:3]1[C:4](=[O:16])[NH:5][C:6]([CH3:15])=[C:7]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[N:10]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-c2nc(C)no2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCc1cc(-c2nc(C)no2)c(C)[nH]c1=O
Temperature: 65 °C
Reaction time: 7 h
Yield: 87 %

Procedure:
To a mixture of 3-ethyl-2-methoxy-6-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl) pyridine (50 mg, 0.215 mmol) and sodium iodide (96 mg, 0.64 mmol) under a nitrogen atmosphere is added anhydrous acetonitrile (4 mL) followed by drop-wise chlorotrimethylsilane (82 μL, 0.653 mmol). The reaction mixture is stirred at 65° C. under nitrogen for 7 hr. The reaction mixture is allowed to cool and then quenched with water (0.5 mL). After stirring for 30 min the mixture is partitioned between water and dichloromethane and the mixture treated with a little sodium bisulfite to decolorize. The dichloromethane layer is separated and the aqueous layer is extracted with four further portions of dichloromethane. The combined organic layer is dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (49:1). Fractions containing the product are combined and the solvent evaporated to give 3-ethyl-6-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyridin-2-one (41 mg, 88% yield) as a white solid. LC/MS: RT: 2.44 min, MS: m/e=220 (M+H); 1H NMR (CDCl3, δ, ppm): 12.49 (1H, s), 7.92 (1H, s), 2.79 (3H, s), 2.61 (2H, q), 2.45 (3H, s), 1.25 (3H, t).
Reaction SMILES: [CH3:1]I.[CH2:3]([O:10][C:11]([N:13]1[CH2:18][C@H:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]3[O:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:25]=3[CH:35]=2)[C@@H:16]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][O:43][CH2:44][C@@H:45]([CH3:49])[CH2:46][O:47][CH3:48])=[CH:38][CH:37]=2)[C@H:15]([CH2:50][OH:51])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+]>>[CH2:3]([O:10][C:11]([N:13]1[CH2:18][C@H:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]3[O:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:25]=3[CH:35]=2)[C@@H:16]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][O:43][CH2:44][C@@H:45]([CH3:49])[CH2:46][O:47][CH3:48])=[CH:38][CH:37]=2)[C@H:15]([CH2:50][O:51][CH3:1])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CO)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](COC)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.568 mmol of methyl iodide are added to a suspension of 0.642 mmol of (3S,4R,5R)-3-hydroxymethyl-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (Example 1a) and 0.963 mmol of sodium hydride (60% dispersion in oil) under argon at 0° C. After stirring for 1 hour at 0° C. and 1 hour at room temperature, the reaction mixture is partitioned between tert-butyl methyl ether and saturated aqueous sodium bicarbonate solution. The aqueous layer is extracted with tert-butyl methyl ether (2×)—the combined organic layers are washed successively with water and brine, dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rf=0.41 (EtOAc-heptane 1:1); Rt=5.87 (gradient I).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1.Br[C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[C:32]#[N:33]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32]#[N:33])=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1Br
Reactant: Oc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of 51.4 g of 4-chlorophenol in 500 ml of dry N,N-dimethylformamide (DMF) was added to a suspension of 20 g of 60% sodium hydride in 800 ml of dry DMF under nitrogen. After 30 min at 25° C., 1 g of 18-crown-6 was added. After the addition of 73 g of 2-bromobenzonitrile in 500 ml of dry DMF, the mixture was heated at 100° C. for 16 h. After concentration in vacuo, 2 N sodium hydroxide and ethyl acetate were added. The organic layer was separated, washed with 2 N sodium hydroxide and water, dried over magnesium sulfate, and evaporated to dryness. The residue was recrystallized from methanol to give in 60% yield 2-(4-chlorophenoxy)benzonitrile. To a suspension of 6 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran (THF) were added under nitrogen 20 of 2-(4-chlorophenoxy)benzonitrile. The mixture was heated at reflux for 3 h, cooled, and 25 ml of 1 N sodium hydroxide were added dropwise. The precipitate formed was filtered off and washed with diethyl ether. The filtrate was evaporated to dryness, dissolved in ethyl acetate and acidified with a saturated solution of hydrochloric acid in ethanol. The precipitate was collected and recrystallized from ethanol to give in 95% yield 2-(4-chlorophenoxy)benzenemethanamine hydrochloride. mp 253° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.CO.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12
Reactant: CN
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Solvent: CO
Product: CNc1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Temperature: 100 °C

Procedure:
A solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (0.8 g, 2.71 mmol) in 40% methylamine in methanol (21 mL, 0.27 mol) was heated under reflux at 100° C. for 4 hours in a sealed stainless tube. The solution was allowed to cool to room temperature, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform:methanol=98:2) to give an oil of N-methyl-N-[3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]amine. To a solution of the oil in ethanol (10 mL), was added a saturated hydrochloric acid/ethanol solution (10 mL), and the solvent was evaporated under reduced pressure. The residue thus obtained was recrystallized from methanol/ethyl acetate to give the title compound (0.63 g, 64% yield).
Reaction SMILES: C(N[C:5]1[CH:6]=[CH:7][C:8]([O:37]CC2C=CC(OC)=CC=2)=[C:9]([CH:36]=1)[C:10](=[O:35])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16](OCC2C=CC=CC=2)=[C:15](OCC2C=CC=CC=2)[CH:14]=1)(=O)C>Cl.C(O)C>[OH:37][C:8]1[CH:7]=[CH:6][CH:5]=[CH:36][C:9]=1[C:10](=[O:35])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(COc2ccc(NC(C)=O)cc2C(=O)C=Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Agent: Cl
Solvent: CCO
Product: O=C(C=Cc1ccccc1)c1ccccc1O
Temperature: 25 °C

Procedure:
A solution of 4′-methoxybenzyloxychalcone (13) (300 mg, 0.489 mmol) in aqueous HCl (2 M, 16 mL) and ethanol (66 mL) was heated at reflux for 1 h. The mixture was cooled to room temperature, and evaporated in vacuo to approximately half the volume. The resultant suspension was filtered to afford the crude deprotected chalcone (14) as a dark yellow solid. The deprotected chalcone was dissolved in 1,4-dioxane (4.8 mL), ethanol (6 mL) and NaOH (5.4% w/v, 1.9 mL) and the resultant solution was cooled in an ice bath and H2O2 (30%, 0.3 mL) was added. The solution was stirred at 0° C. for 2 h, and subsequently at room temperature overnight. The solution was then acidified with 2 M HCl and the precipitate that formed was filtered, and then recrystallised from THF/petroleum spirits to afford the flavonol (15) as a yellow solid (136 mg, 55%), m.p. 229-230° C. Anal. Calcd. for C31H25NO6: C, 73.36; H, 4.96; N, 2.76. Found: C, 73.38; H, 4.98; N, 2.68%. 1H NMR (399.7 MHz, d6-DMSO) δ 2.09 (s, 3H, CH3); 5.21, 5.24 (2 s, 2×2H, 2×CH2); 7.26 (d, 1H, J5′,6′ 8.8 Hz, H5′); 7.33-7.52 (m, 11H, 2×Ph); 7.71 (d, 1H, J7,8 9.2 Hz, H8); 7.84-7.92 (m, 3H, H2′,6′,7); 8.40 (d, 1H, J5,7 2.4 Hz, H5); 9.48 (br s, 1H, OH); 10.27 (s, 1H, NH). 13C NMR (100.5 MHz, d6-DMSO) δ 24.03 (1C, CH3); 69.91, 70.43, 112.65, 112.69, 113.79, 118.89, 121.38, 121.91, 124.06, 125.32, 135.91, 136.88, 137.08, 138.14, 145.14, 147.77, 149.77, 150.42 (18C, Ar); 168.59, 172.47 (2C, 2×C═O).
Reaction SMILES: [CH:1]1([N:4]2[CH2:8][CH2:7][NH:6][S:5]2(=[O:10])=[O:9])[CH2:3][CH2:2]1.F[C:12]1[C:21]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:26])[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(=O)OCC>CN(C=O)C>[CH:1]1([N:4]2[S:5](=[O:10])(=[O:9])[N:6]([C:12]3[C:21]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:26])[CH:13]=3)[CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S1(=O)NCCN1C1CC1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(N2CCN(C3CC3)S2(=O)=O)cc1C
Yield: 47.3 %

Procedure:
203 mg of 2-cyclopropyl-[1,2,5]thiadiazolidine 1,1-dioxide, 308 mg of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate and 2.44 g of Cs2CO3 were stirred in 25 ml of anhydrous DMF at 80° C. for 5 hours. Standing at RT for 2 days was followed by dilution with 200 ml of EA and washing 3 times with 20 ml of water each time. After drying over Na2SO4, the solvent was removed in vacuo. Chromatography on silica gel with DIP afforded 230 mg of an amorphous solid.