Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)CCCNC(NC1SC(C2C=CC(S(C)(=O)=O)=C(F)C=2)=C(C)N=1)=O)C.[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[S:44][C:43]([NH2:45])=[N:42][C:41]=2[CH3:46])=[CH:36][C:35]=1[C:47]([F:50])([F:49])[F:48])(=[O:33])=[O:32].[CH2:51]([O:53][C:54](=[O:60])[CH2:55][CH2:56][N:57]=[C:58]=[O:59])[CH3:52]>>[CH2:51]([O:53][C:54](=[O:60])[CH2:55][CH2:56][NH:57][C:58]([NH:45][C:43]1[S:44][C:40]([C:37]2[CH:38]=[CH:39][C:34]([S:31]([CH3:30])(=[O:32])=[O:33])=[C:35]([C:47]([F:50])([F:49])[F:48])[CH:36]=2)=[C:41]([CH3:46])[N:42]=1)=[O:59])[CH3:52]
Reactant: CCOC(=O)CCN=C=O
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)s1

Procedure:
The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine (158a) and replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[O:21]=[C:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:31][CH:32]=[O:33])[CH:28]=2)[NH:23]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:31][CH:32]=[O:33])[CH:28]=2)[NH:23][C:22]1=[O:21]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: O=CNc1ccc2c(c1)CC(=O)N2
Product: Cc1c(C=C2C(=O)Nc3ccc(NC=O)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 87.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-formamide as starting materials to give N-{3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-formamide (48 mg, 87.9%) as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([OH:9])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH2:25]>ClCCl>[CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([NH:25][NH:24][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:9]
Reactant: Cc1scnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1scnc1C(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-methyl-1,3-thiazole-4-carboxylic acid (500 mg, 3.49 mmol) in dry dichloromethane (DCM) (17.500 ml) was stirred at room temperature under an atmosphere of argon. EDC (736 mg, 3.84 mmol) and HOBt (267 mg, 1.746 mmol) were added to the stirred solution and the resulting solution was stirred at room temperature for ½ hour. After this time, 1,1-dimethylethyl hydrazinecarboxylate (554 mg, 4.19 mmol) was added and the solution was stirred for a further 16 hours (overnight) at room temperature. The solution was diluted with DCM (approx. 50 ml) and washed with water (2× approx. 25 ml). The organics were dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow coloured oily solid. The residue was chromatographed [SiO2, MeOH in DCM 0-5%] to give a pale yellow coloured solid of desired material in 544 mg.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]([CH2:15]Br)[C:9]=2[C:17]=1[CH3:18])(=[O:3])[CH3:2].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>CN(C)C=O>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]([CH2:15][N:25]3[C:24](=[O:26])[C:23]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]4[C:21]3=[O:31])[C:9]=2[C:17]=1[CH3:18])(=[O:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(CBr)C(C)(C)O2
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(CN1C(=O)c3ccccc3C1=O)C(C)(C)O2
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of 4.75 g of 5-acetoxy-3-bromomethyl-2,3-dihydro-2,2,4,6,7-pentamethyl-1-benzofuran (see Example 3) and 2.58 g (1 equivalent)of potassium phthalimide in 50 ml of dry dimethylformamide is stirred at 60° C. for 48 hours. Water is added and the product is extracted twice with ethyl ether. The extract is washed with water and brine, and is dried over anhydrous sodium sulfate. After filtration, evaporation of the solvent leaves a residue that is crystallized from ethyl acetate/heptane. The first crop contains free phthalimide, but subsequent crops yield 2,3-dihydro-2,2,4,6,7-pentamethyl-3-phthalimidomethyl-1-benzofuran-5-ol acetate.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18](=[O:30])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([OH:28])=[C:23]([F:29])[CH:22]=1)C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:24]3[C:23]([F:29])=[CH:22][C:21]([CH2:20][CH2:19][C:18]([OH:30])=[O:17])=[CH:26][C:25]=3[F:27])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: ClCc1cccnc1SC1CCCC1
Product: O=C(O)CCc1cc(F)c(OCc2cccnc2SC2CCCC2)c(F)c1
Yield: 79.4 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.037 g, 0.16 mmol) obtained in Step C of Preparation Example 8 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.037 g, 0.16 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.050 g, 79%).
Reaction SMILES: I[CH3:2].[CH:3]1([CH:6]([OH:33])[C:7]2[N:11]3[CH2:12][C@H:13]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=4[F:32])[CH2:14][CH2:15][C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]3=[N:9][CH:8]=2)[CH2:5][CH2:4]1.[H-].[Na+]>O1CCCC1>[CH:3]1([CH:6]([O:33][CH3:2])[C:7]2[N:11]3[CH2:12][C@H:13]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=4[F:32])[CH2:14][CH2:15][C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]3=[N:9][CH:8]=2)[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(O)C3CC3)cnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
Iodomethane (9.0 μL, 0.15 mmol) was added to a solution of tert-butyl (6S,9R)-3-[cyclopropyl(hydroxy)methyl]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (66 mg, 0.15 mmol) and sodium hydride (60% dispersion in mineral oil; 8.3 mg, 0.23 mmol) in tetrahydrofuran (1 mL) at 0° C. After 1 h, the mixture was allowed to warm to ambient temperature. After 2 h, additional iodomethane (6.0 μL, 0.10 mmol) and sodium hydride (60% dispersion in mineral oil; 3.0 mg, 0.08 mmol) were added. After 1 h, the reaction was quenched with water and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (23 mg). MS 448.2 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:24])=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[C:17]([CH3:23])=[N:18][O:19][C:20]=1[CH2:21][OH:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:24])=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[C:17]([CH3:23])=[N:18][O:19][C:20]=1[CH:21]=[O:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1noc(CO)c1-c1ccnc(F)c1CO[Si](C)(C)C(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1noc(C=O)c1-c1ccnc(F)c1CO[Si](C)(C)C(C)(C)C
Temperature: 50 °C

Procedure:
To a solution of (4-(3-((tert-butyldimethylsilyloxy)methyl)-2-fluoropyridin-4-yl)-3-methylisoxazol-5-yl)methanol (1.35 mg, 8.83 mmol) in CH2Cl2 (38 mL) at room temperature was added manganese dioxide (6.66 g, 77 mmol). The heterogeneous reaction was heated to 50° C. in a sealed tube for 2 h. The reaction was then cooled to room temperature and filtered. Then the solid was rinsed with EtOAc and the filtrate was concentrated to dryness under vacuum. The residue was used without any purification in the next step. LC/MS m/z 351 [M−H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:18])=[C:6]([C:8]([C:10]2[C:15](F)=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[O:9])[CH:7]=1.C[C:20]([O:23]C)(C)C.C[O-].[Na+].CO>C(O)C(C)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:18])=[C:6]([C:8]([C:10]2[C:15]([O:23][CH3:20])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[O:9])[CH:7]=1
Reactant: O=C(c1cc(Cl)ccc1I)c1c(F)cccc1F
Reactant: COC(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)CO
Solvent: O
Product: COc1cccc(F)c1C(=O)c1cc(Cl)ccc1I
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Into a reactor at room temperature was added 2 (67.6 kg, 179 mol) and MTBE (344 L). The mixture was warmed to 40° C. and stirred for 30 min until solids fully dissolved. The mixture was then cooled to 25 to 30° C. Sodium methoxide as a 25% w/w solution in methanol (45.2 kg, 209 mol) was added over a minimum of 90 min at 25 to 30° C. The reaction mixture was stirred for at least 2 h until >99.0% conversion was obtained by HPLC analysis. Water (483 L) was added slowly over 30 min while maintaining the temperature between 20 and 25° C. The layers were separated and the aqueous phase was extracted with MTBE (77 L). The combined organic extracts were washed with a dilute brine solution (38 kg NaCl in 342 L water). The organic layer was filtered, washed with water (242 L) and the organic phase was filtered. The resulting organic phase was concentrated until 360 L of solvent were removed while maintaining the internal temperature below 70° C. Isobutanol (302 L) was added and the mixture was concentrated while maintaining the internal temperature below 70° C. until 307 L of solvent were removed. A second portion of isobutanol (330 L) was added and the mixture was concentrated while maintaining the internal temperature below 70° C. until 210 L of solvent were removed. The mixture was heated to 60 to 85° C. until a clear solution was obtained and cooled to 50° C. A slurry of seed crystals (50 g in 150 mL isobutanol) was added and the mixture was cooled to 40° C. A second slurry of seed crystals (30 g in 60 mL isobutanol) was added and the mixture was cooled to 20 to 25° C. over a minimum of 3 h. The resulting mixture was stirred an additional 2 h. The mixture was filtered and washed with isobutanol (2×65 L). The resulting wet cake was dried at 20 to 35° C. under vacuum to provide 50.9 kg of crude 3. Into a separate reactor was charged crude 3 and isobutanol (69 L). The mixture was heated to 75 to 80° C. until a clear solution was obtained. The reaction mixture was cooled to 55° C. and a slurry of seed crystals (50 g in 500 mL isobutanol) was added. The mixture was stirred for 30 min at 55° C., cooled to 20 to 25° C. over a minimum of 3 h and stirred an additional 2 h. The mixture was filtered and washed with isobutanol (2×31 L). The wet cake was dried under vacuum at 40° C. to provide 46.0 kg (66% yield) of purified 3. 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=8.2 Hz, 1H), 7.42 (m, 2H), 7.13 (dd, J=2.3, 8.2 Hz), 6.76 (m, 2H), 3.73 (s, 3H); MS (ESI) m/z 391.2 (M+H+, 30%).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[K].[F:7][C:8]1[C:9](=[S:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=1>CN(C)C=O>[CH2:1]([S:15][C:9]1[C:8]([F:7])=[CH:13][NH:12][C:11](=[O:14])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=c1[nH]cc(F)c(=S)[nH]1
Reactant: CCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCSc1nc(=O)[nH]cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 20 %

Procedure:
n-Butyl bromide (0.007 mol) was added to a solution of the potassium salt of 5-fluoro-4-thiouracil (0.006 mol) in dimethylformamide (30 ml) and the reaction mixture was stirred at room temperature for 3 days before evaporation at reduced pressure (1 mm Hg). The desired product was isolated from the residue by preparative paper chromatography (Whatman No. 3) using butanol:ethanol:ammonia:water (4:1:2:1); yield 20%, m.p. 113° C. (H2O). (Found: C, 47.20; H, 5.30. Calc. for C8H11FN2OS: C, 47.52; H, 5.48).
Reaction SMILES: O1CCCC1.C1(C)C=CC(S(O[CH2:16][CH:17]2[S:29][C:21]3=[N:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:20]3[CH2:19][CH2:18]2)(=O)=O)=CC=1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32].[H-].[Na+]>O>[CH2:31]([N:33]([CH2:16][CH:17]1[S:29][C:21]2=[N:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:20]2[CH2:19][CH2:18]1)[CH2:34][CH3:35])[CH3:32]
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CC1CCn2c(nc3ccccc32)S1
Yield: 40 %

Procedure:
Into 20 ml of tetrahydrofuran was dissolved 1.12 g (3 m mole) of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole, followed by the addition of 5 ml of diethylamine. Then, a catalytic amount of sodium hydride was added under ice-cooled stirring conditions. The temperature of the mixture was allowed to rise to room temperature andthen refluxed for eight hours. The reaction mixture was cooled and then condensed under reduced pressure. The reaction product was added with water and then extracted with chloroform. The chloroform layer was then dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and elutedwith chloroform to obtain 0.33 g (yield: 40%) of the intended product, m.p.93°-94° C.; IR νmaxKBr cm-1 : 3100-2800, 1420; Anal. Calcd. for C15H21N3S: C, 65.42; H, 7.68; N, 15.26; S, 11.64; Found: C, 65.33; H, 7.77; N, 15.49; S, 11.41.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:28]=[C:29]([N+:34]([O-])=O)[C:30]([NH2:33])=[N:31][CH:32]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[Sn](Cl)Cl>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[N:31][CH:32]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1
Reactant: Cc1ncnc(N2CCOc3ccc(-c4cnc(N)c([N+](=O)[O-])c4)cc3C2)c1Cc1ccc(F)cc1
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Product: Cc1ncnc(N2CCOc3ccc(-c4cnc(N)c(N)c4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 50 °C
Yield: 61.3 %

Procedure:
To a solution of 5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3-nitropyridin-2-amine (0.36 g, 0.75 mmol) in acetic acid (10 mL) was added tin (II) chloride (0.75 g, 3.8 mmol). The reaction mixture was heated (50° C.) for 2 h and then partitioned between ethyl acetate (10 mL) and 1 N aqueous sodium hydroxide (20 mL). The resulting mixture was filtered through Celite and the organic layer was washed with brine (10 mL), dried over anhydrous magnesium sulfate then filtered and concentrated. Column chromatography on silica (5% methanol/dichloromethane) provided 5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridine-2,3-diamine (0.21 g, 60% yield) as a pale yellow solid. MS (EI) for C26H25FN6O: 457 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1.CN([C:23]([CH:25]=[CH2:26])=O)C.FC(F)(F)C(O)=O>>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][N:6]1[C:2]2=[N:1][CH:23]=[CH:25][CH:26]=[C:3]2[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:5]1
Reactant: C=CC(=O)N(C)C
Reactant: CCOC(=O)c1cc(N)n(Cc2ccccc2F)n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Reaction time: 72 h

Procedure:
The solution obtained from 2A) is mixed with 61.25 ml (60.77 g, 0.613 mmol) of dimethylaminoacrolein and 56.28 ml (83.88 g, 0.736 mol) of trifluoroacetic acid and boiled under argon for 3 days. The solvent is then evaporated in vacuo, and the residue is added to 21 of water and extracted three times with 11 of ethyl acetate each time. The combined organic phases are dried over magnesium sulfate and concentrated in a rotary evaporator. Chromatography is carried out on 2.5 kg of silica gel, eluting with a toluene/toluene-ethyl acetate=4:1 gradient. Yield: 91.6 g (49.9% of theory over two stages).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[CH:18][N:19]=[C:13]3[CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.CC1(C)C(C)(C)[O:24][B:23](B2OC(C)(C)C(C)(C)O2)[O:22]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[N:19]1[CH:18]=[CH:17][N:14]2[CH:15]=[CH:16][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([B:23]([OH:24])[OH:22])[N:3]=3)=[CH:12][C:13]=12
Reactant: Cn1cc(Br)nc(Nc2ccn3ccnc3c2)c1=O
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1cc(B(O)O)nc(Nc2ccn3ccnc3c2)c1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 185a (638 mg, 1.99 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (Pin2B2, 2.54 mg, 10 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (163 mg, 0.18 mmol), Cs2CO3 (1.3 g, 3.98 mmol), and 1,4-dioxane (20 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 80° C. under nitrogen atmosphere for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with petroleum ether (150 mL) and ethyl acetate (15 mL). The resulting suspension was stirred at room temperature for 30 minutes. The solid was collected by filtration and further purified by silica-gel column chromatography eluting with dichloromethane/methanol (60/1 to 15/1) to afford 185b (400 mg, 70%) as an off-white solid. MS-ESI: [M+H]+ 286
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([CH2:46][C:47]([NH:49][CH3:50])=[O:48])[CH:43]=[CH:44][CH:45]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:44]2[CH:45]=[CH:40][CH:41]=[C:42]([CH2:46][C:47]([NH:49][CH3:50])=[O:48])[CH:43]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CNC(=O)Cc1cccc(Br)c1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CNC(=O)Cc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 23.5 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.47 g), 2-(3-bromophenyl)-N-methylacetamide (0.93 g) and tetrakis(triphenylphosphine)palladium(0) (0.21 g), the title compound (580 mg) was obtained as colorless powder crystals.
Reaction SMILES: [CH2:1]([S:9](Cl)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[O:27]=[C:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][S:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:11])=[O:10])=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: CCCCCCCCS(=O)(=O)Cl
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Product: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 1-octanesulfonyl chloride and 1-(4-amino-phenyl)-piperidine-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, J=5.4 Hz, 3H), 1.15-1.40 (m, 10H), 1.60-1.75 (m, 2H), 2.40 (t, J=4.5 Hz, 4H), 2.94 (t, J=5.7 Hz, 2H), 3.54 (t, J=4.5 Hz, 4H), 6.99 (d, J=6.9 Hz, 2H), 7.09 (d, J=6.9 Hz, 2H), 9.31 (s, 1H); MS (ES) m/z: 367.0 (MH+); HRMS Calcd. for C19H30N2O2S(M+): 366.1977. Found: 366.1969. Anal. Calcd. for C19H30N2O2S: C, 62.26; H, 8.25; N, 7.64. Found: C, 62.40; H, 7.98; N, 7.59.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([CH:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>C(O)C.O1CCCC1.ClCCl>[CH:16]1([CH2:15][CH:14]([C:12]2[NH:11][C:8]3=[N:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]3[CH:13]=2)[C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)nc3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (110 mg, 0.25 mmol) in ethanol (4 mL) and tetrahydrofuran (4 mL), was treated with an aqueous sodium hydroxide solution (10%, 1.5 mL) and stirred at 50° C. for 1 h. The mixture was acidified to pH 4-5 with a 2N aqueous hydrochloric acid solution, diluted with dichloromethane (150 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (100 mg, 94%) as a white solid which was used in the next step without further purification: LC/MS m/e calcd for C21H23N3O4S [M+H]+ 414.50, observed 414.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)C.[ClH:16].O1CCOCC1.[NH3:23]>CO>[ClH:16].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11](=[NH:23])[NH2:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCO
Product: N=C(N)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 22 h

Procedure:
A suspension of (4-nitrophenyl)acetonitrile (4.86 g, 30.0 mmol) in ethanol (6 mL, 99 mmol) in a 250 mL round bottom flask was slowly treated at room temperature with 4N hydrochloric acid in dioxane (38 mL, 152 mmol) and stirred for 22 hours. After carefully removing the solvent under water aspirator vacuum at 40° C. the obtained wet pale yellow product was suspended in 21 mL ethanol. Then, a 7N ammonia solution in methanol (12 mL, 84 mmol) was slowly added giving a pale gray suspension. After stirring for two hours additional 2 mL (14 mmol) 7N ammonia solution in methanol were added. After further stirring for one hour at room temperature all volatiles were removed under water aspirator vacuum at 40° C. To remove residues of ethanol and dioxane methyl t-butyl ether (30 mL) was added and once more all volatiles were removed under water aspirator vacuum at 40° C. giving an off-white solid. The crude product was used without purification in the next step.