Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10])(=[O:3])[CH3:2].[Br:16]Br>O1CCOCC1>[Br:16][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([NH:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH:7]=[CH:8][C:9]=1[Cl:10])=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cc(NS(C)(=O)=O)ccc1Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(Cl)c(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-acetyl-4-chlorophenyl)methanesulfonamide (300 mg) was dissolved in dioxane (5 mL), and bromine (77 μL) was added dropwise with ice-cooling. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was washed with a water/ethanol mixture (1:1) and then dried under reduced pressure to yield N-(3-bromoacetyl-4-chlorophenyl)methanesulfonamide (312 mg) as a colorless crystal.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26][C:27]1[CH:51]=[CH:50][C:30]([C:31]([NH:33][C:34]2[C:35]([C:40]([NH:42][C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][N:44]=3)=[O:41])=[N:36][CH:37]=[CH:38][CH:39]=2)=[O:32])=[C:29](O)[CH:28]=1>>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([NH:42][C:40]([C:35]2[C:34]([NH:33][C:31](=[O:32])[C:30]3[CH:29]=[CH:28][C:27]([S:26][CH3:25])=[CH:51][C:50]=3[O:12][CH2:11][C@@H:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:39][CH:38]=[CH:37][N:36]=2)=[O:41])=[N:44][CH:45]=1
Reactant: CSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Reactant: COc1ccc(CO[C@H](CO)CNC(=O)OC(C)(C)C)cc1OC
Product: COc1ccc(CO[C@@H](CNC(=O)OC(C)(C)C)COc2cc(SC)ccc2C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)cc1OC
Yield: 71 %

Procedure:
Using a procedure analogous to Example 38-D, (2S)-3-(t-butoxycarbonylamino)-2-(3,4-dimethoxybenzyloxy)propanol and 3-[4-methylthio-2-(hydroxy)benzoylamino]-N-(5-chloro-pyridin-2-yl)pyridine-2-carboxamide gave the title compound as a solid (800 mg, 71%).
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=O.[C:23]([CH2:25][C:26]([NH2:28])=[O:27])#[N:24].Cl>CN(C=O)C.CO>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[NH:28][C:26](=[O:27])[C:25]([C:23]#[N:24])=[CH:5][C:6]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][CH:13]=1
Reactant: N#CCC(N)=O
Reactant: Cc1ccc(C(=O)C(=CN(C)C)c2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(-c2[nH]c(=O)c(C#N)cc2-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a slurry of NaH (1.38 g, 60% in mineral oil, 34.41 mmol) in DMF (20 mL) at 0° C. was added a solution of 3-(dimethylamino)-1-(4-methylphenyl)-2-phenylprop-2-en-1-one (1-2; 4.15 g, 15.64 mmol) and 2-cyanoacetamide (1.45 g, 17.2 mmol) in MeOH (1.5 mL) and DMF (40 mL) dropwise over 40 min. The resulting mixture was stirred at 90° C. for 4 h and cooled to rt. The mixture was poured into dilute HCl aqueous solution (240 mL, 0.25 M) and filtered, washed with water (40 mL) and dried in vacuo to afford 6-(4-methylphenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (1-3). 1H-NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 7.15-7.28 (m, 7H), 7.05-7.07 (m, 2H), 2.36 (s, 3H). LRMS m/z (M+H) Calcd: 287.3, found: 287.1.
Reaction SMILES: [CH3:1][CH:2]([C:8](=[O:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:11]Br>O>[Br:11][CH2:9][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: BrBr
Reactant: CCOC(=O)C(C)C(C)=O
Solvent: O
Product: CCOC(=O)C(C)C(=O)CBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-methyl-3-oxobutanoate (5.05 g, 35.0 mmol) in water (10 mL) at 0° C. was added bromine (1.81 mL, 35.0 mmol) dropwise over 2 h. The resulting solution was stirred at rt for 16 h. The reaction mixture was extracted with ethyl acetate, the organic phase was dried over sodium sulfate and concentrated to give ethyl 4-bromo-2-methyl-3-oxobutanoate. 1HNMR (500 MHz, CDCl3), δ4.322-4.274 (m, 2H), 2.455 (s, 2H), 1.991 (s, 3H), 1.337-1.309 (t, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11])C.O1CCCC1.B.Cl.O>C1COCC1>[OH:11][CH2:10][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][OH:3])[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCc1cccc(C(=O)O)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1cccc(CO)c1
Reaction time: 18 h
Yield: 80.5 %

Procedure:
Under a nitrogen atmosphere, to a solution of 3-(3-ethoxy-3-oxopropyl)benzoic acid (2.99 g) in THF (100 mL) was added a 1.0 M solution of tetrahydrofuran-borane in tetrahydrofuran (26.9 mL) at 0° C., and the mixture was stirred in an ice bath for 18 hr. A 1.0 M solution of tetrahydrofuran-borane in tetrahydrofuran (20.0 mL) was added at 0° C., and the mixture was further stirred for 20 hr in an ice bath. 1N Hydrochloric acid (100 mL) and water were added at 0° C., and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.80 g) as a colorless oil.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[C:19]([CH3:20])=[C:18]([CH3:21])[S:17][C:16]=1[C:22]([OH:24])=O.[NH2:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1>O1CCCC1>[CH3:13][O:14][C:15]1[C:19]([CH3:20])=[C:18]([CH3:21])[S:17][C:16]=1[C:22]([NH:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)=[O:24]
Reactant: Nc1nnn[nH]1
Reactant: COc1c(C(=O)O)sc(C)c1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1c(C(=O)Nc2nnn[nH]2)sc(C)c1C
Reaction time: 2.5 h
Yield: 72.4 %

Procedure:
1,1'-Carbonyldiimidazole (4.1 g, 25 mmoles) is added to a solution of 3-methoxy-4,5-dimethyl-2-thiophenecarboxylic acid (4.5 g, 24 mmoles) in tetrahydrofuran (80 mL) under argon. The mixture is stirred and heated under reflux for 1.5 hours. 5-Aminotetrazole (2.0 g, 24 mmoles) is added and heating under reflux is continued for an additional 2.5 hours. The mixture is cooled, and the precipitate is filtered off, rinsed with tetrahydrofuran, dried, and stirred in 2N HCl. After 10 minutes the suspended solid is collected by filtration, rinsed with water and dried to afford the product (4.4 g); mp 229° C. (dec).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:16]4=[N:23][NH:24][C:25](=[O:26])[C:15]4=[CH:14]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[N:37]1([C:34]2[CH:35]=[CH:36][C:31]([CH2:30][N:24]3[C:25](=[O:26])[C:15]4=[CH:14][N:13]([CH2:12][C:9]5[CH:10]=[CH:11][C:6]([N:1]6[CH:5]=[CH:4][CH:3]=[N:2]6)=[CH:7][CH:8]=5)[C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[C:16]4=[N:23]3)=[CH:32][CH:33]=2)[CH:41]=[CH:40][CH:39]=[N:38]1
Reactant: BrCc1ccc(-n2cccn2)cc1
Reactant: O=c1[nH]nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc1-2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1Cc1ccc(-n2cccn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5-{[4-(1H-Pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 406, 71 mg, 0.21 mmol) was suspended in degassed N,N-dimethylformamide (3 mL), cooled to 0° C. and sodium hydride (17 mg, 0.42 mmol, 2 equiv, 60% dispersion in mineral oil) was added. After stirring for 10 minutes at 0° C., the mixture was warmed to ambient temperature and stirred for 45 minutes. 1-[4-(Bromomethyl)phenyl]-1H-pyrazole (74 mg, 0.31 mmol, 1.5 equiv) was added, the mixture as stirred for 2 hours and then poured into sodium bicarbonate (30 mL, aqueous saturated) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 88:12; dichloromethane:methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.09 (1H, s), 8.45-8.44 (2H, m), 8.15 (1H, d, J=7.8 Hz), 7.82-7.78 (4H, m), 7.75-7.72 (2H, m), 7.57 (1H, t, J=7.8 Hz), 7.48 (1H, t, J=7.7 Hz), 7.45-7.40 (4H, m), 6.52 (2H, s), 5.75 (2H, s), 5.14 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 498.2063 [(M+H)+; calculated for C30H24N7O: 498.2037].
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21](COCC[Si](C)(C)C)[N:20]=[C:19]2[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:14])=[O:13])(=[O:5])=[O:4].[OH-].[Na+]>C(O)C.C(OC(C)C)(C)C>[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:14])=[O:13])(=[O:5])=[O:4]
Reactant: C[Si](C)(C)CCOCn1nc(CCc2ccccc2)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(CCc3ccccc3)c2c1
Temperature: 20 °C
Yield: 29.9 %

Procedure:
2-Methylsulfonyl-N-(3-phenethyl-1H-indazol-5-yl)benzenesulfonamide can be obtained in the following way: 5.6 ml of an aqueous 5N hydrochloric acid solution are added dropwise to a suspension of 0.56 g of 2-methylsulfonyl-N-[3-phenethyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]benzenesulfonamide in 17 ml of absolute ethanol. The reaction mixture is then refluxed for 30 minutes and then cooled to a temperature in the region of 20° C. 6.8 ml of an aqueous 5N sodium hydroxide solution are then added and the mixture is stirred. The mixture is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and the residue is taken up in a mixture of 35 ml of ethyl acetate and of 50 ml of water. After settling out, the aqueous phase is extracted with 2 times 30 ml of ethyl acetate. The organic extracts are pooled, washed with 2 times 20 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue thus obtained is purified by chromatography under argon pressure (50 kPa) on a column of 75 g of silica (particle size 40-63 μm), eluting with a dichloromethane/methanol (98/2 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue thus obtained is repurified by chromatography under argon pressure (50 kPa), on a column of silica (particle size 40-63 μm), eluting with a cyclohexane/ethyl acetate (70/30 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue thus obtained is taken up in 15 ml of diisopropyl ether, triturated, filtered and then dried. 130 mg of 2-methylsulfonyl-N-(3-phenethyl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a white solid melting at 192° C. (Cl mass analysis: m/z 456 (M+H)+).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24](=[O:43])[C:25]([NH2:42])([CH3:41])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:43])[C@@:25]([NH:42][C:12](=[O:14])[C@@H:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])([CH3:41])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)C(C)(N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)N[C@](C)(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 38 %

Procedure:
A solution of the product from Example Z ((2S)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.5 g, 1.95 mmol) and the product from Example D (2-amino-2-methyl-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.73 g, 2.15 mmol) were coupled according to the procedure described in Example 3. The two diastereomeric products were separated by chromatography (silica gel, 1:1 heptane/EtOAc) to give a high Rf product as a white solid (0.43 g, 38%), mp=46-49° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Si:11]([O:18][CH2:19][CH:20]([C:22]1[CH:23]=[C:24]([C:29]2[N:34]=[C:33]([CH3:35])[N:32]=[C:31]([NH2:36])[N:30]=2)[C:25](F)=[N:26][CH:27]=1)[CH3:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[F:37][C:38]1[CH:39]=[C:40]([NH2:46])[CH:41]=[N:42][C:43]=1[O:44][CH3:45]>C1COCC1>[Si:11]([O:18][CH2:19][CH:20]([C:22]1[CH:23]=[C:24]([C:29]2[N:34]=[C:33]([CH3:35])[N:32]=[C:31]([NH2:36])[N:30]=2)[C:25]([NH:46][C:40]2[CH:41]=[N:42][C:43]([O:44][CH3:45])=[C:38]([F:37])[CH:39]=2)=[N:26][CH:27]=1)[CH3:21])([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: COc1ncc(N)cc1F
Reactant: Cc1nc(N)nc(-c2cc(C(C)CO[Si](C)(C)C(C)(C)C)cnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)CO[Si](C)(C)C(C)(C)C)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
Sodium bis(trimethylsilyl)amide (1.0M in THF) (Aldrich, St. Louis, Mo.; 1.279 mL, 1.279 mmol) was added to an orange-brown solution of 4-(5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (201.2 mg, 0.533 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, North Brunswick, N.J.; 91 mg, 0.640 mmol) in THF (5.0 mL) at 0° C., and the resulting brown solution was stirred at 0° C. for 1.5 h. Additional sodium bis(trimethylsilyl)amide (1.0M in THF) (Aldrich, St. Louis, Mo.; 0.300 mL, 0.300 mmol) was then added, and the resulting mixture was stirred at 0° C. for 30 min. Excess sodium bis(trimethylsilyl)amide was carefully quenched with saturated aqueous NH4Cl (5 mL), and the resulting mixture was partitioned between CH2Cl2 (50 mL) and half-saturated aqueous NH4Cl (30 mL). The aqueous layer was extracted with CH2Cl2 (30 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 70% EtOAc/hexanes) furnished 4-(5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (241.0 mg, 0.482 mmol, 91% yield) as a yellow-orange solid. 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.73 (d, J=2.5 Hz, 1H), 8.26 (dd, J=12.3, 2.2 Hz, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.04 (d, J=2.3 Hz, 1H), 5.40 (br. s., 2H), 4.02 (s, 3H), 3.67 (dd, J=6.2, 2.8 Hz, 2H), 2.91 (q, J=6.5 Hz, 1H), 2.57 (s, 3H), 1.32 (d, J=7.0 Hz, 3H), 0.87 (s, 9H), 0.00 (s, 3H), −0.01 (s, 3H). 19F NMR (377 MHz, CDCl3) δ −139.42 (s, 1 F). m/z (ESI, +ve) 500.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].C1(C)C=CC(S(O[CH2:26][CH2:27][O:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([O:35][CH2:36][C:37]3[N:38]=[C:39]([C:43]4[CH:44]=[C:45]([CH3:49])[CH:46]=[CH:47][CH:48]=4)[O:40][C:41]=3[CH3:42])[CH2:30]2)(=O)=O)=CC=1>CN(C=O)C.[Na+].[Cl-].C(OCC)(=O)C>[CH3:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:2]([O:1][CH2:26][CH2:27][O:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([O:35][CH2:36][C:37]3[N:38]=[C:39]([C:43]4[CH:44]=[C:45]([CH3:49])[CH:46]=[CH:47][CH:48]=4)[O:40][C:41]=3[CH3:42])[CH2:30]2)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1c(C)cccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@@H]2CCC[C@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cccc1OCCO[C@@H]1CCC[C@H](OCc2nc(-c3cccc(C)c3)oc2C)C1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
90 mg of ethyl 2-hydroxy-6-methylbenzoate are dissolved in 2 ml of dry DMF, and 23 mg of a 60 percent strength sodium hydride suspension are added. After 30 min at room temperature, 100 mg of ((1R,3S)-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl toluene-4-sulfonate in 2 ml of DMF are added. The mixture is stirred at 40° C. until the reaction has gone to completion (monitored by LC-MS). After cooling, the mixture is diluted with sat. NaCl solution and ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. This gives ethyl (1R,3S)-2-methyl-6-{2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethoxy}benzoate as a yellowish oil. C30H37NO6 (507.63), MS (ESI): 508 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CC(C)=O>O>[CH2:34]([O:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([C:5]2[C:6]([NH:8][C:9]3[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[CH3:17])=[N:7][C:2]([CH3:1])=[N:3][CH:4]=2)(=[O:20])=[O:19])=[CH:26][CH:25]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(O)cc2)c(C)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.3 %

Procedure:
A mixture of 4-[2-methyl-4-(2,4,6-trimethylphenylamino)-pyrimidine-5-sulfonyl]-phenol (56 mg, 0.15 mmol), prepared as described in Example 2, potassium carbonate (40 mg, 29 mmol), benzyl bromide (0.034 mL, 0.29 mmol) and acetone (3 mL) was stirred at room temperature under N2 for 48 h. The reaction mixture was diluted with water, and extracted (3×) with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (50:50 hexanes/EtOAc) to provide the target compound (62 mg, 91%) as a white solid: mp 166–168° C.; 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.20 (br s, 1H), 7.87 (d, J=8.8 Hz, 2H), 7.36–7.40 (m, 5H), 7.05 (d, J=8.8 Hz, 2H), 6.91 (s, 2H), 5.12 (s, 2H), 2.39 (s, 3H), 2.31 (s, 3H), 2.00 (s, 6H); ESI MS m/z 474 [(M+H)+, calcd for C27H28N3O3S, 474.2].
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.Br[CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:23][C:24]#[N:25])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: N#CCBr
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCC#N)cc3=O)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (3.0 g), bromoacetonitrile (0.82 ml), potassium carbonate (4.42 g) and DMF (10 ml) was stirred at 80° C. for 2 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc). The resulting solid was washed with IPE to give the title compound (2.39 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14](=O)[CH2:15]Br)=[CH:12][CH:11]=[C:10]([O:18][CH3:19])[C:8]=2[N:9]=1.[C:21]([NH2:24])(=[S:23])[CH3:22]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[N:24]=[C:21]([CH3:22])[S:23][CH:15]=3)=[CH:12][CH:11]=[C:10]([O:18][CH3:19])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C(=O)CBr)c2s1
Reactant: CC(N)=S
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)Nc1nc2c(OC)ccc(-c3csc(C)n3)c2s1
Reaction time: 4 h

Procedure:
1.3 g of (7-bromoacetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester (0.0036 Mol) and 0.27 g of thioacetamide (0.0036 Mol) were dissolved in dioxane (30 ml) and stirred for 4 hrs. at 70° C. After evaporation of half of the solvent water (40 ml) was added and the pH adjust to 7 with sat. NaHCO3. A solid precipitated, which was isolated and then subjected to column chromatography on silicagel using ethyl acetate as eluent. The title product was isolated as an off-white solid (27%); F.p.: 186-188° C.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.Cl.Cl[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[CH2:13][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)c1cc(O)no1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccc3ccccc3n2)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A mixture of methyl 3-hydroxyisoxazole-5-carboxylate (5.01 g), 2-chloromethylquinoline hydrochloride (8.99 g), potassium carbonate (14.50 g) and N,N-dimethylformamide (100 ml) was stirred at 60° C. for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-(2-quinolylmethoxy)-5-isoxazolecarboxylate (7.78 g, yield 78%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran. The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 133–134° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.CC(C)([O-])C.[K+].Cl.Cl[C:21]1[CH:26]=[CH:25][NH+:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:5]=1
Reactant: Clc1cc[nH+]cc1
Reactant: COC(OC)c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)c1cccc(Oc2ccncc2)c1
Temperature: 25 °C

Procedure:
A solution of 1 g of 3-hydroxybenzaldehyde dimethyl acetal and 2 g of potassium tert.butoxide in 10 ml of anhydrous dimethylformamide was heated at 60° C. under an atmosphere of dry nitrogen for 1 hour. The mixture was then cooled to room temperature and 900 mg of 4-chloropyridinium hydrochloride were added portionwise over a period of 20 minutes. The mixture was then heated at 160° C. for 18 hours, cooled, 100 ml of water were added and the product was extracted with ethyl acetate. The combined extracts were washed with 1M aqueous sodium hydroxide solution and with brine, and then dried over anhydrous magnesium sulphate. Evaporation to dryness left a brown oil which was purified by column chromatography on silica gel using hexane/ethyl acetate (gradient: 90:10 to 20:80) for the elution to give 3-(4-pyridyloxy)-benzaldehyde dimethyl acetal as a light brown oil.