Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].Br[C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1.Cl>O>[CH3:1][NH:2][C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1
Reactant: CS(=O)(=O)Nc1cc2occ(Br)c(=O)c2cc1Oc1ccccc1
Reactant: CN
Agent: Cl
Solvent: O
Product: CNc1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Reaction time: 2 h
Yield: 11.1 %

Procedure:
50 ml of a 25% aqueous methylamine solution was ice-cooled. Thereto was added 4.1 g of 3-bromo-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. The mixture was stirred for 2 hours at 0°-5° C. 100 ml of water was added thereto. The mixture was adjusted to pH 4 with 4N hydrochloric acid and then extracted with 100 ml of ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 5:1 mixture of toluene and ethyl acetate) and then recrystallized from ethanol to obtain 400 mg (yield: 11.1%) of 3-methylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [CH2:1]([C:4]([CH2:10][CH2:11][CH3:12])([CH2:7][O:8][CH3:9])[CH2:5][OH:6])[CH2:2][CH3:3].[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>>[CH2:10]([C:4]([CH2:1][CH2:2][CH3:3])([CH2:5][O:6][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH2:7][O:8][CH3:9])[CH2:11][CH3:12]
Reactant: C[Si](C)(C)Cl
Reactant: CCCC(CO)(CCC)COC
Product: CCCC(CCC)(COC)CO[Si](C)(C)C

Procedure:
According to the procedure as described in Example 1,2,2-di-n-propyl-1-methoxy-3-[(trimethylsilyl)oxy]propane was prepared from intermediate 2,2-di-n-propyl-3-methoxy-1-propanol and reagent trimethylsilyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[N:6][C:7]=1[C:8]#[N:9].[NH2:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:8]([C:7]1[N:6]=[CH:5][C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:3][C:2]=1[NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Br)c1
Reactant: Cc1cc(C)nc(N)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)c1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a flask were added tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate (21.5 g, 54.4 mmol), 2-amino-4,6-dimethylpyridine (9.97 g, 81.7 mmol), Pd2(dba)3 (2.49 g, 2.72 mmol), Xantphos (3.15 g, 5.44 mmol), cesium carbonate (35.4 g, 109 mmol) and dioxane (215 mL). The mixture was degassed by bubbling nitrogen through the reaction mixture. After 15 minutes, the nitrogen purge was ceased and the reaction mixture was heated to 80° C. After 5 hours, the reaction mixture was cooled to ambient temperature, and filtered through CELITE (washing with ethyl acetate). To the filtrate was added silica gel, and the solvent was removed under reduced pressure. The residue was purified via silica gel chromatography to afford tert-butyl [(1S,2R)-2-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate. MS ESI calc'd. for C24H33N6O2 [M+H]+ 437. found 437. 1H NMR (600 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.52 (s, 1H), 6.60 (s, 1H), 6.54 (d, J=8.4 Hz, 1H), 6.53 (s, 1H), 6.33 (d, J=7.2 Hz, 1H), 3.71 (s, 1H), 3.55 (s, 1H), 2.56 (s, 3H), 2.16 (s, 3H), 1.74-1.66 (m, 1H), 1.64-1.54 (m, 2H), 1.51-1.42 (m, 3), 1.32-1.23 (m, 10), 1.12-1.08 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[NH2:35][CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][C:39]1=[O:43]>>[O:43]=[C:39]1[CH2:40][CH2:41][CH2:42][N:38]1[CH2:37][CH2:36][NH:35][C:29](=[O:30])[CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:34])([F:33])[F:1])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[CH3:32]
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: NCCN1CCCC1=O
Product: CC(C(=O)NCCN1CCCC1=O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoro ethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 1-(2-aminoethyl)pyrrolidin-2-one (Matrix and Cat. No. 016683). LCMS (M+H)+: m/z=584.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:12]=[C:11](S(C)(=O)=O)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:29]#[N:30].[Na+]>CS(C)=O.ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:12]=[C:11]([C:29]#[N:30])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1nc(OCc2ccccc2)cc(-c2cccc(C(F)(F)F)c2)n1
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1nc(OCc2ccccc2)cc(-c2cccc(C(F)(F)F)c2)n1
Yield: 67.5 %

Procedure:
4-Benzyloxy-2-methanesulfonyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (92 mg) and sodium cyanide (22 mg) were stirred at room temperature in dimethylsulphoxide (500 μl) for 20 minutes. The reaction mixture was diluted with dichloromethane (40 ml) and washed with water (3×50 ml). Organics were separated, dried over sodium sulphate and solvent was evaporated under reduced pressure to yield crude product (86 mg) as a yellow oil. Purification by flash chromatography on silica gave product 4-benzyloxy-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (54 mg).
Reaction SMILES: Cl[CH:2]([C:6](=[O:8])[CH3:7])[C:3](=[O:5])[CH3:4].[Cl:9][C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[C:14]([Cl:16])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[O:17][CH:2]([C:6](=[O:8])[CH3:7])[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)C(Oc1cc(Cl)cc(Cl)c1)C(C)=O
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
3-Chloro-2,4-pentanedione (183 μL, 1.53 mmol)) was added to a stirred suspension of 3,5-dichlorophenol (250 mg, 1.53 mmol) and potassium carbonate (233 mg, 1.69 mmol) in acetone (7.7 ml) at room temperature under nitrogen. The mixture was stirred for 30 minutes and then heated under reflux for 3½ hours. After cooling, sodium iodide (230 mg, 1.53 mmol) was added and refluxing continued for a further 3½ hours. After cooling again the mixture was diluted with water (5 ml) and concentrated under reduced pressure in a fumehood (Caution: possible residual lachrymator) to remove acetone. The resulting red aqueous solution was diluted with 2M hydrochloric acid (5 ml) and extracted with dichloromethane (3×10 ml). The combined organic layers were washed with saturated aqueous sodium sulphite solution (10 ml) and brine (10 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to leave a red oil (344 mg). The crude product was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (20:1, by volume) to give the title compound (118 mg) as a cream solid m.p. 91-92° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:17]1[C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=[CH:19][C:18]=1[C:26]([OH:28])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:23]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([C:26]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:28])[N:17]=1)=[O:25])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)c1cccc(C(=O)O)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)c1cccc(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)n1
Yield: 76.9 %

Procedure:
Using General Procedure A with 5.8 g (24.0 mmol) D-Proline benzyl ester hydrochloride and 2.0 g (12.0 mmol) pyridine-2,6-dicarboxylic acid afforded, after flash chromatography (EtOAc), 5.0 g (77%) of the title compound as a yellow oil. MS m/e (%): 559 (M+NH4+, 60), 542 (M+H+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH3:43])C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:45])[CH:10]=1)#[N:2].C[Mg]Br>O1CCCC1>[F:45][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:44])[N:18]([C@H:28]2[CH2:29][CH2:30][C@H:31]([O:34][CH:35]([CH3:43])[C:31]([OH:34])([CH3:32])[CH3:30])[CH2:32][CH2:33]2)[C:19]2[N:20]([N:25]=[CH:26][N:27]=2)[C:21]=1[CH2:22][CH2:23][CH3:24]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(=O)OC(C)(C)C)CC2)c2ncnn12
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2ncnn12
Reaction time: 1 h

Procedure:
tert-Butyl 2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanoate (548 g) was dissolved in tetrahydrofuran (2.7 L), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 3.5 L) was added with the internal temperature maintained below 10° C. The reaction mixture was stirred at the same temperature for 1 hr, and partitioned among saturated aqueous ammonium chloride solution (600 mL), water (600 mL) and ethyl acetate (500 mL). The aqueous layer was extracted with ethyl acetate (1 L). The combined extracts were washed with saturated brine (1 L), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound as a racemate (428 g, 84%).
Reaction SMILES: O1CC1CO[N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[C:17]1([CH:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:31]1([CH:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:17][CH:23]([OH:24])[CH2:31][C:15]3[CH:14]=[CH:13][CH:12]=[C:9]4[C:10]([NH:6][C:7](=[O:16])[C:8]=34)=[O:11])[CH2:27][CH2:26]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1c2ccccc2C(=O)N1OCC1CO1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Solvent: CCO
Product: O=C1NC(=O)c2c(CC(O)CN3CCC(OC(c4ccccc4)c4ccccc4)CC3)cccc21

Procedure:
3.70 g of potassium phthalimide was dissolved in 20 ml of N,N-dimethylformamide; 2.58 ml of epibromohydrin was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure; ethyl ether was added to the residue; the crystal precipitated was collected to yield 3.7 g of N-(2-oxiranylmethoxy)phthalimide. 0.61 g of N-(2-oxiranylmethoxy)phthalimide and 0.802 g of 4-(diphenylmethoxy)piperidine were dissolved n 10 ml of ethanol, followed by thermal refluxing for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected to yield 1.30 g of N-[3-[4-(diphenylmethoxy)piperidino-2-hydroxypropyl]phthalimide as an oily substance. This oily substance was dissolved in 10 ml of ethanol; 0.14 ml of hydrazine monohydrate was added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure; ethanol was added to the residue; the crystal precipitated was collected, dissolved in 3 ml of a 1 N aqueous solution of sodium hydroxide and 10 ml of water and extracted with ethyl acetate; the extract was washed with saline, dried over sodium sulfate and concentrated under reduced pressure; the crystal obtained was collected to yield 0.76 g of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:7][N:8]([C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)[C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: CNc1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a stirred solution of butyryl chloride (0.770 g, 7.23 mmol) in chloroform ( 15 mL) was added N-methyl-4-nitroaniline and triethylamine (1.2 mL, 8.6 mmol). After overnight stirring, additional butyryl chloride (0.40 mL, 3.9 mmol) was added and the reaction was refluxed for 2-3 hours. The reaction was concentrated and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was combined with a second ethyl acetate extract, dried (sodium sulfate) and concentrated. The resulting dirty yellow oil was purified by flash chromatography over silica (methylene chloride/methanol) to afford 1.11 g (76%) of product as a pale yellow solid: 1H NMR (CDCl3) δ 8.30 (d, J=8.9 Hz, 1H), 7.40 (d, J=8.9 Hz, 1H), 3.34 (s, 3H), 2.18 (t, J=7.5 Hz, 2H), 1.71-1.59 (m, 2H), 0.88 (t, J=7.6Hz,
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[C:33]([O:40][CH3:41])[CH:32]=5)[O:28][N:27]=4)[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:7][C:8]([CH2:16][N:17]1[C:25]2[C:20](=[C:21]([C:26]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[C:33]([O:40][CH3:41])[CH:32]=4)[O:28][N:27]=3)[CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CCOc1ccc(-c2nc(-c3cccc4c3ccn4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OC
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC(N)(CO)CO)no2)cc1OC
Yield: 83 %

Procedure:
When the product of Step E was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 83% yield, as white solid. 1H-NMR (CDCl3: CD3OD) 1.43 (tr, 3H, J=6.98 Hz); 3.14 (s, 2H); 3.24-3.5 (m, 4H); 3.58 (d, 2H, J=11.87 Hz); 3.64 (d, 2H, J=11.63 Hz); 3.91 (s, 3H); 4.1 (q, 2H, J=14, 7.02 Hz); 6.75 (d, 1H, J=7.78 Hz); 6.91 (d, 1H, J=8.54 Hz); 7.17 (tr, 1H, J=7.98 Hz); 7.41 (d, 1H, J=7.75 Hz), 7.6 (s, 1H); 7.71 (d, 1H, J=1.86, 8.49 Hz).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[CH2:15][CH3:16]>>[CH2:15]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:16]
Reactant: CCI
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Product: CCn1c2ccccc2c2ccccc21

Procedure:
Carbazole (4 g, 0.024 mol) was reacted with iodoethane by working in a similar manner to Example 1a).
Reaction SMILES: [OH:1]O.[C:3]([C:5]1[C:6]([CH3:17])=[C:7]([C:12]([S:15][CH3:16])=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:4].[OH-].[Na+]>C(O)C.O>[CH3:11][O:10][C:8]([C:7]1[C:6]([CH3:17])=[C:5]([CH:14]=[CH:13][C:12]=1[S:15][CH3:16])[C:3]([NH2:4])=[O:1])=[O:9]
Reactant: OO
Reactant: COC(=O)c1c(SC)ccc(C#N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)c1c(SC)ccc(C(N)=O)c1C
Temperature: 65 °C

Procedure:
Hydrogen peroxide (30%, 18 ml) was added dropwise with stirring to a solution of methyl 3-cyano-2-methyl-6-methylsulphenylbenzoate (10.0 g) in ethanol (100 ml) in an atmosphere of nitrogen. A solution of sodium hydroxide (0.43 g) in water (2 ml) was added dropwise and the resultant rapid exotherm was controlled by ice cooling. After the exotherm had ceased the mixture was stirred and heated at 65° C. for 0.5 hours. The orange solution was poured into a mixture of ice and water (400 ml) and it was extracted with ether (3×100 ml). The combined organic extracts were washed with water (100 ml), aqueous ferrous sulphate solution (100 ml), water (2×100 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 3-methoxycarbonyl-2-methyl-4-methylsulphenylbenzamide (4.2 g) as an orange oil, NMR (CDCl3) 2.3(s,3H), 2.4(s,3H), 3.9(s,3H), 6.5(bs,2H), 6.95(d,1H), 7.25(d,1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:17][CH3:18])=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:8].[SH:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[S:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:17][CH3:18])=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:8]
Reactant: Sc1nc2ccccc2o1
Reactant: CSc1nc(C)ccc1NC(=O)CCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(C)ccc1NC(=O)CCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
Triethylamine (475 mg, 4.7 mmol) was added to a chloroform (10 ml) solution of this aminopyridine (601 mg, 3.9 mmol), and 6-bromohexanoyl chloride (944 mg, 4.29 mmol) was then slowly added thereto dropwise while being cooled with ice, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 50 g, eluent—hexane:ethyl acetate=10:1→5:1) to obtain 773 mg (yield 59%) of 6-bromo-N-(6-methyl-2-methylthio-3-pyridyl)hexanamide as a colorless crystal (melting point: 98 to 99° C.). To a DMF (2 ml) solution of this amide (133 mg, 0.4 mmol) and 2-mercaptobenzoxazole (67 mg, 0.44 mmol) were added 18-crown-6 (11 mg, 0.04 mmol) and potassium carbonate (67 mg, 0.44 mmol), and the mixture was stirred at 80° C. for 90 minutes. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 20 g, eluent—hexane:acetone=5:1→5:3) to obtain 125 mg (yield 78%) of the desired compound as a colorless needle crystal.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.OC[CH:24]1[CH2:29][N:28](S(C2C=CC3C(=CC=C(Br)C=3)C=2)(=O)=O)[CH2:27][CH2:26][NH:25]1.C(N(CC)CC)C>ClCCl.O.CN(C=O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:24]3)=[O:13])=[CH:14][CH:15]=2)=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNC(CO)C1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(-c2ccncc2)cc1)N1CCNCC1
Reaction time: 2 h
Yield: 119.9 %

Procedure:
A stirred suspension of 4-(4-pyridyl)benzoic acid (sodium salt) (190 mg, 0.86 mmol) in dichloromethane (10 ml) was treated with oxalyl chloride (0.2 ml, 2.3 mmol) and DMF (catalytic amount). After stirring for 2 hours, further oxalyl chloride 0.2 ml, 2.3 mmol) and DMF (catalytic amount) was added and the suspension stirred a further 4 hours. The solvent was removed in vacuo and the residue, after drying, was suspended in dichloromethane (20 ml) and treated with 2-(hydroxymethyl)-4-(6-bromonaphth-2-ylsulphonyl)piperazine (300 mg, 0.78 mmol) and triethylamine (0.36 ml, 2.5 mmol). After stirring at room temperature overnight the reaction mixture was diluted with dichloromethare (20 ml) and water (20 ml). A copious precipitate appeared which was filtered off, dried and recrystallised from ethyl acetate (10 ml) to yield 1-(6-bromonaphth-2-ylsulphonyl)-3hydroxymethyl)-4-[4-(4-pyridyl)benzoyl]piperazine as a colourless solid (250 mg); 1H NMR (300 MHz, DMSO-d6) δ=3-4 ppm (broad, 9H), δ=7.2 ppm (d, 2H), δ=7.7 ppm (d, 2H), δ=7.8 ppm (m, 4H), δ=8.2 ppm (t, 2H), δ=8.4 ppm (s, 1H), δ=8.45 ppm (s, 1H), δ=8.6 ppm (d, 2H); signals due to ethyl acetate (1 mol eq) were also present; MS: (M+H)+ 566/568 (1 Br pattern); analysis; found: C, 56.8; H, 4.9; N, 6.3%; C27H24BrN3SO4.C4H8O2 requires: C, 56.9; H, 4.9; N, 6.4%.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:22])([O:14][C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[C:4]([OH:23])=[O:3])=[CH:12][CH:11]=3)[N:34]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)cc1
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(C4CCCCC4)oc3C)cc2)C(=O)O)cc1

Procedure:
The representative procedure (B) was utilized to prepare the title compound from 3-(4-hydroxyphenyl)-2-methyl-2-p-tolyloxypropionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 10.90 (bs, 1H), 7.18 (d, 2H, J=8.4 Hz), 7.05 (d, 2H, J=8.4 Hz), 6.79 and 6.79 (d of Abq, 4H, J=8.0 Hz), 4.15 (t, 2H, J=6.0 Hz), 3.23 and 3.11 (d of Abq, 2H, J=13.8 Hz), 3.02-2.93 (m, 3H), 2.34 (s, 3H), 2.29 (s, 3H), 2.10-2.00 (m, 2H), 1.89-1.80 (m, 2H), 1.77-1.70 (m, 1H), 1.64-1.51 (m, 2H), 1.45-1.19 (m, 3H), 1.38 (s, 3H). IR (KBr) 3450, 1734, 1509, 1228 cm−1. HRMS (ES+) m/z exact mass calcd for C29H36NO5 478.2593, found 478.2613.