Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[I-].[K+].[Cl:8][C:9]1[CH:10]=[C:11]([S:16][C:17]2[NH:21][C:20]([CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[N:19][C:18]=2[CH:33]([CH3:35])[CH3:34])[CH:12]=[C:13]([Cl:15])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:3]([CH2:2][N:21]1[C:17]([S:16][C:11]2[CH:12]=[C:13]([Cl:15])[CH:14]=[C:9]([Cl:8])[CH:10]=2)=[C:18]([CH:33]([CH3:34])[CH3:35])[N:19]=[C:20]1[CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)CCl
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
(1)In acetone (2 ml)was dissolved 111 mg (1.20 mmol)of chloroacetone, followed by addition of 200 mg (1.2 mmol)of potassium iodide, and the mixture was stirred at room temperature for 15 minutes. Then, 437 mg (1.00 mmol)of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (16b)and 170 mg (1.20 mmol)of potassium carbonate were added in order, and the mixture was stirred for 5 hours and was left overnight. This reaction mixture was concentrated under reduced pressure and the residue was extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure. The residue was fractionated by silica gel chromatography (ethyl acetate:methylene chloride=1:9). The oil was crystallized from ether to provide 270 mg (yield 62%)of 1-acetylmethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (17v). mp 87-90° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][S:32]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][S:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)(=[O:34])=[O:33])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: O=S(=O)(Nc1ccccc1Br)N1CCOCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3NS(=O)(=O)N3CCOCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 571 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and N-(2-bromophenyl)morpholine-4-sulfonamide. MS (ESI): mass calcd. for C20H20FN5O3S, 429.13; m/z found, 430.4 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.63 (d, J=1.2, 2H), 7.70-7.54 (m, 2H), 7.48-7.25 (m, 5H), 3.70-3.55 (m, 4H), 3.05 (dd, J=5.7, 3.8, 4H).
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:17]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=4)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:30]>C(O)C.[Pd]>[ClH:30].[F:29][C:24]1[CH:23]=[C:22]([C:17]2[C:18]3[C:19]4[CH2:20][CH2:21][NH:8][CH2:9][CH2:10][C:11]=4[NH:12][C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH:27]=[C:26]([F:28])[CH:25]=1
Reactant: Fc1cc(F)cc(-c2cccc3[nH]c4c(c23)CCN(Cc2ccccc2)CC4)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Fc1cc(F)cc(-c2cccc3[nH]c4c(c23)CCNCC4)c1
Yield: 46.5 %

Procedure:
A mixture of 3-benzyl-10-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.35 g, 0.90 mmol), 1 N hydrochloric acid (0.9 mL, 0.9 mmol) and Pd/C (10%, 0.5 g) in ethanol (50 mL) was reacted in a manner similar to Example 8 to give 0.14 g of the title compound as a cream-colored solid: m p>267° C. (dec.); 1H NMR (400 MHz, DMSO-d6) δ 11.42, 9.57, 7.37, 7.30-7.25, 7.11-7.07, 6.84, 6.78-6.76, 3.35-3.27, 3.25-3.18, 3.16-3.08, 2.63-2.56; IR (drift) 3259, 2956, 2861, 2811, 2778, 2699, 2641, 2455, 1622, 1591, 1458, 1332, 1113, 985, 749 cm−1; HRMS (FAB) calcd for C18H16F2N2+H: 299.1360, found: 299.1369.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:10][CH:11]1[CH:15]([CH3:16])[C:14](=[O:17])[O:13][S:12]1(=[O:19])=[O:18]>>[C:1]([O:6][CH2:7][CH2:8][O:9][C:14](=[O:17])[CH:15]([CH3:16])[CH:11]([S:12]([OH:19])(=[O:18])=[O:13])[CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCO
Reactant: CC1C(=O)OS(=O)(=O)C1C
Product: C=C(C)C(=O)OCCOC(=O)C(C)C(C)S(=O)(=O)O
Yield: 70 %

Procedure:
By procedure 9)a) above, β-hydroxyethyl methacrylate is reacted with an equimolar amount of 3,4-dimethyl-1,2-oxathiolane-5-one-2,2-dioxide. There is obtained a 70% yield of methacryloxyethyl-2-methyl-3-sulfo-butyrate.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]([CH3:12])[O:10][CH2:9][CH2:8][N:7]1CC1C=CC=CC=1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([CH3:12])[O:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(C)OCCN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1NCCOC1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of the crude 4-benzyl-2-methyl-morpholine-3-carboxylic acid ethyl ester (Comp. No. 26) obtained in the preceding experiment in methanol (10 ml) was treated with a catalytic amount of palladium on charcoal (10% w/w; 25 mg). The flask was flushed with hydrogen and the hydrogen atmosphere was maintained whilst stirring at room temperature. After 5 h, the catalyst was removed by filtration, the solution was treated with a new amount of palladium on charcoal (10% w/w; 25 mg) and the hydrogen atmosphere was restored. Stirring was continued for a further 96 h. The catalyst was filtered off, washed with methanol and the combined filtrates were concentrated in vacuo to give 0.140 g of 2-methyl-morpholine-3-carboxylic acid ethyl ester, which was used in the next step without further purification. LC/MS (method 7): Rt=0.45 min; m/z=174.15 (M+H+).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:9]=[C:10](Cl)C=O)([O-:5])=[O:4].S(=O)(=O)(O)O>O1CCOCC1>[N+:3]([C:6]1[CH:7]=[C:8]([C:9]#[CH:10])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])([O-:5])=[O:4]
Reactant: O=CC(Cl)=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C#Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
To 50 ml of a rapidly stirred 0.5 m sodium hydroxide solution maintained at 60° C was rapidly added a solution containing 4.0 g (15.5 mmoles) of 3,4-dinitro-α-chlorocinnamaldehyde dissolved in 10 ml of dioxane. The mixture was stirred for 5 minutes, at which time the solution was cooled and neutralized with 1N sulfuric acid. The reaction mixture was extracted into methylene chloride, and the combined extracts washed with several portions of water. The methylene chloride solution was reduced in volume to 25 ml and filtered through a 1 × 3 inch dry column of silica gel, eluting with methylene chloride. Evaporation of the eluate yielded 1.2 g (40% yield) of 3,4-dinitroethynyl benzene as a light brown oil.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].I[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[OH:3][C:1]([C:4]1[S:8][C:7]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[CH:6][CH:5]=1)([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(=O)n(C)c2)s1
Reactant: Ic1ccncc1
Product: Cn1cc(-c2ccc(C(C)(O)c3ccncc3)s2)ccc1=O
Yield: 21.3 %

Procedure:
Using 5-(5-acetylthiophen-2-yl)-1-methylpyridin-2(1H)-one (0.07 g, 0.3 mmol), 4-iodopyridine (0.12 g, 0.6 mmol), and the procedure described for example 7 and step 4, crude compound was obtained and further purified by preparative TLC (5% methanol in dichloromethane) to give 5-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)thiophen-2-yl)-1-methylpyridin-2(1H)-one as off-white solid (0.02 g, 21% yield) in 99.8% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.48 (d, 2H), 7.97 (d, 1H), 7.65 (dd, 1H), 7.45-7.44 (t, 2H), 7.07 (d, 1H), 6.94 (d, 1H), 6.41-6.38 (m, 2H), 3.42 (s, 3H), 1.85 (s, 3H); LC-MS m/z calculated for [M+H]+ 313.09. found 313.1.
Reaction SMILES: B(Br)(Br)Br.[I:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16]C)[CH:12]=2)[CH:7]=1.O>ClCCl>[I:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH:7]=1
Reactant: COc1ccc2cc(I)ccc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2cc(I)ccc2c1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 93.3 %

Procedure:
BBr3 (102 g, 407 mmol) is added dropwise over 30 min to a slightly cloudy solution/suspension of 2-iodo-6-methoxy-naphthalene (45.4 g, 160 mmol) in dichloromethane (dried over 3 {acute over (Å)} molecular sieves) (1 L) at −8° C. The mixture is warmed to 20° C. and stirred at this temp for 1.5 h. Water (400 mL) is carefully added (slow dropwise addition at the start) and the biphasic mixture vigorously stirred for 20 min. The layers are separated and the aqueous layer extracted with dichloromethane (250 mL) with additional water (400 mL) being added. The combined organic fractions are washed with water (500 mL), dried (Na2SO4), filtered and solvent removed in vacuo to give a colourless solid with silvery purple patches (44.7 g). This is recrystallised from IMS/water (initially dissolved in 100 mL IMS) washing with water and dried in a vacuum oven to give an off-white solid (40.3 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C3CCCC3)c3c(Cl)cccc23)cc1
Yield: 49 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.129 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and cyclopentylbromide (0.107 mL, 1.0 mmol) to give the title compound (0.080 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([O:18]CC)=[O:17])[C:13](=[O:21])[C:12]([CH3:23])([CH3:22])[C@@H:11]([OH:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13](=[O:21])[C:12]([CH3:22])([CH3:23])[C@@H:11]([OH:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)CN1C(=O)C(C)(C)[C@@H](O)C[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(CC(=O)O)[C@H](c2cc(F)cc(F)c2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl [(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate from Step C (64 mg, 187 mmol) in THF (1 mL) and H2O (0.5 mL) was added LiOH monohydrate (14 mg, 334 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. The reaction mixture was quenched with 1 N HCl (0.40 mL, 400 mmol), concentrated in vacuo and dried to afford the title compound. MS: m/z=314 (M+1).
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[CH:17][C:16]=2[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[Si:30]([O:29][C:16]1[CH:17]=[C:18]([O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23])[CH:19]=[CH:20][C:15]=1[C@H:12]1[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]1)([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 18 h

Procedure:
To a round bottom flask was added trans-N-benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy} phenyl) cyclohexyl]amine (500 mg, 0.95 mmol) and ethanol (20 ml). To the stirred solution was added palladium (10% w/w on activated carbon, 200 mg, 0.19 mmol) as a slurry in ethanol (5 ml). The reaction vessel was evacuated, then placed under hydrogen (10 cycles). The reaction mixture was stirred vigorously under an atmosphere of hydrogen for 18 hr, then filtered through a celite plug, washing with methanol (100 ml). The solvent was removed in vacuo affording the desired product (402 mg, 97%) as a colourless oil. δH(CDCl3) 0.01 (6H, s), 0.05 (6H, s), 0.78 (9H, s), 0.82 (9H, s), 1.08 (2H, m), 1.21 (2H, m), 1.62 (2H, m), 1.78 (2H, m), 2.59 (2H, m), 6.11 (1H, d), 6.22 (1H, dd), 6.78 (1H, d).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=3[N+:27]([O-])=O)[CH:13]=[CH:14][CH:15]=2)=[N:5][CH:4]=[N:3]1.[H][H]>C(O)C.O=[Pt]=O>[CH3:1][N:2]1[C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17]3[C:18]([NH2:27])=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=3)[CH:13]=[CH:14][CH:15]=2)=[N:5][CH:4]=[N:3]1
Reactant: [H][H]
Reactant: Cn1ncnc1COCc1cccc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CCO
Product: Cn1ncnc1COCc1cccc(Nc2ccc(C(F)(F)F)cc2N)c1

Procedure:
To a solution of 19a (0.6 g, 1.5 mmol) in ethanol (20 ml) was added platinium oxide (0.15 g) and the resultant mixture was hydrogenated at ambient pressure until the hydrogen uptake had ceased. Filtration through celite and concentration of the filtrate in vacuo left 20a, which was taken directly into the next step. The following compounds were prepared in analogy herewith: N1-[3-(2-Ethyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-4-trifluoromethyl-benzene-1,2-diamine (20b) from 19b 4-Methyl-N1-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-benzene-1,2-diamine (20c) from 19c 1-{3-Amino-4-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenylamino]-phenyl}-ethanone (20d) from 19d
Reaction SMILES: CO.[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[C:12]([C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)=[O:29])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]2[CH2:25][O:24]C(C)(C)[O:22]2)[CH:16]=1)=[O:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O>[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[C:12]([C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)=[O:29])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([OH:22])[CH2:25][OH:24])[CH:16]=1)=[O:14]
Reactant: CC1(C)OC[C@@H](c2cccc(C(=O)C(C(=O)c3cccc(F)c3)=C3Nc4ccccc4N3)c2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(C(C(=O)c1cccc([C@@H](O)CO)c1)=C1Nc2ccccc2N1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.7 %

Procedure:
A 20 ml portion of methanol solution containing 1.68 g of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-{3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]phenyl}-3-(3-fluorophenyl)propane-1,3-dione was mixed with 560 mg of p-toluenesulfonic acid monohydrate and stirred at room temperature for 18 hours. This was mixed with appropriate amounts of purified water and saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate and dried with anhydrous magnesium sulfate. After concentration, the thus formed residue was purified by a silica gel column chromatography to obtain 640 mg (42%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-{3-[(1R)-1,2-dihydroxyethyl]phenyl}-3-(3-fluorophenyl)propane-1,3-dione (Example 4-1) from a hexane-ethyl acetate (3:1-1:3) eluate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[CH:14]=[CH:13][N:12]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.[NH2:30][C@@H:31]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][C:33]([OH:35])=[O:34].C([O-])([O-])=O.[Na+].[Na+].Cl>C1COCC1.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:30][C@@H:31]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][C:33]([OH:35])=[O:34])[CH:14]=[CH:13][N:12]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(S(C)=O)n3)c3cc(F)cnc32)cc1
Reactant: CC(C)(C)[C@H](N)CC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(N[C@H](CC(=O)O)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Temperature: 125 °C
Yield: 31 %

Procedure:
A mixture of 5-fluoro-3-(4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 127a, (0.052 g, 0.121 mmol) and (3R)-3-amino-4,4-dimethyl-pentanoic acid, 2a, (0.035 g, 0.242 mmol) along with Na2CO3 (0.051 g, 0.483 mmol) in a mixture of THF (0.780 mL) and acetonitrile (0.260 mL) was heated to 125° C. for 30 minutes under microwave irradiation. Then, the temperature was raised to 150° C. for a further 2.5 hours. The mixture was neutralized with aqueous 2N HCl and extracted with several portions of EtOAc. The organic solvents were evaporated in vacuo. Purification by flash chromatography (SiO2, 0-100% hexanes-EtOAc (with 10% MeOH)) provided 19 mg of the desired material (31% yield), which was used in the next step without further purification: LCMS Gradient 10-90%, 0.1% trifluoroacetic acid, 5 minutes, C18/ACN, RT=2.70 minutes (M+H) 512.00.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][CH2:6][C:7]1([CH3:27])[O:11][N:10]=[C:9]([S:12][CH2:13][C:14]2[C:15]([C:23]([F:26])([F:25])[F:24])=[N:16][N:17]([CH2:21][CH3:22])[C:18]=2[O:19]C)[CH2:8]1.C(Cl)(Cl)Cl>ClCCl>[Cl:5][CH2:6][C:7]1([CH3:27])[O:11][N:10]=[C:9]([S:12][CH2:13][C:14]2[C:15]([C:23]([F:26])([F:25])[F:24])=[N:16][N:17]([CH2:21][CH3:22])[C:18]=2[OH:19])[CH2:8]1
Reactant: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
10 ml of boron tribromide (2 M/liter of dichloromethane solution, 20.2 mmoles) was added, at −60° C., into a solution of 2.5 g (6.7 mmoles) of 5-chloromethyl-3-(1-ethyl-5-methoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-meth-yl-2-isoxazoline dissolved in 30 ml of dichloromethane. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into ice water and extraction with chloroform was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.6 g (yield: 66.7%) of 5-chloromethyl-3-(1-ethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13]3[C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:19]C(C)([O-])C.[K+].CI>C1COCC1>[CH3:19][N:7]1[C:6]2[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:14]=2[C:13]2[C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1cccc2c1c1c(n2C)CCCC1=O
Reaction time: 0.5 h
Yield: 178.8 %

Procedure:
To a solution of methyl 4-oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate (0.27 g, 1 mmol) in THF (5 ml) at 0° C. under N2 was added potassium t-butoxide (0.12 g, 1.05 mmol). The reaction mixture was stirred for 30 minutes followed by the addition of methyl iodide (0.76 g, 5.0 mmol). After 3 hours, the reaction mixture was concentrated to a residue and partitioned between EtOAc (40 ml) and 1N HCl (5 ml). The layers were shaken and separated. The organic layer was washed with 1N HCl (2×80 ml) and brine (2×10 ml), dried over Na2SO4, filtered, and concentrated to give a solid (0.46 g). The solid was used in the next step without further purified. 1H NMR (DMSO-d6) δ 7.35-7.39 (m, 2H), 7.29 (t, 1H, J=7.2 Hz), 4.01 (s, 3H), 3.72 (s, 3H), 2.93-2.95 (m, 2H), 2.54-2.56 (m, 2H), and 2.23-2.26 (m, 2H). MS (ESI) m/e [M+1]+ 258.0
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=1.O>CN(C=O)C>[I:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1
Reactant: Nc1ccc(I)cc1
Reactant: COc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccnc(Nc2ccc(I)cc2)n1
Temperature: 125 °C
Reaction time: 21 h
Yield: 14 %

Procedure:
Under an argon atmosphere, sodium hydride (100 mg) was added to a solution of 4-iodoaniline (220 mg) and 2-chloro-4-methoxypyrimidine (145 mg) in anhydrous DMF (10 ml), and the resulting mixture was stirred at 125° C. for 21 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extracting the resulting mixture with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:hexane/ethyl acetate=10/1) to obtain N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg). (2) Under an argon atmosphere, N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg) was added to a suspension of sodium hydride (11 mg) in anhydrous DMF (5 ml), and the resulting mixture was stirred at room temperature for 5 minutes. Methyl iodide (0.0096 ml) was added dropwise to the reaction solution, and the resulting mixture was stirred at room temperature for 23 hours. Water was added thereto and the resulting mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:hexane/ethyl acetate=3/1) to obtain N-(4-iodophenyl)-4-methoxy-N-methylpyrimidin-2-amine (46 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:38]4[C:37](=[CH:36][CH:35]=[C:34]([CH3:33])[CH:39]=4)[NH:40][C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccccc3)c(CCCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-4-piperidinyl]phenyl}propanamide and 1-(4-methylphenyl)hydrazine hydrochloride: ESMS m/e: 508.3 (M+H)+.