Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:11][N:10]([CH3:25])[CH:9]=1.ClC1C=CC=CC=1CC(=O)CC1C=CC=C(C(F)(F)F)C=1.C(OCC)=O.Cl.CN.N1C=CC=CC1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13](=[O:14])[CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=2)[CH2:11][N:10]([CH3:25])[CH2:9]1
Reactant: Cn1cc(-c2cccc(C(F)(F)F)c2)c(=O)c(-c2ccccc2Cl)c1
Agent: CN
Agent: Cl
Agent: O=C(Cc1cccc(C(F)(F)F)c1)Cc1ccccc1Cl
Solvent: CCOC=O
Product: CN1CC(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2Cl)C1

Procedure:
Ten g. of 3-(2-chlorophenyl)-1-methyl-5-(3-trifluoromethylphenyl)-4(1H)-pyridinone was prepared from 35 g. of 1-(2-chlorophenyl)-3-(3-trifluoromethylphenyl)-2-propanone by reaction with ethyl formate and methylamine hydrochloride as described in Examples 1-3. The pyridinone was reduced with 2 g. of lithium aluminum hydride and excess hydride was decomposed and the product worked up and chromatographed as described in Examples 1-3. The recovered yields were about 1.3 g. of a mixture of the compounds of Examples 21 and 22, which were identified by mass spectroscopy with an indicated molecular weight of 365. About 2.1 g. of the compound of Example 23 was recovered, m.p. 90°-92°. The elemental analysis of Example 23 was as follows.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.[H-].[Na+].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[O:27][CH:28]=1.O>CN(C=O)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]4[CH:6]=[CH:7][N:8]=[C:4]4[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=3)[N:25]=2)=[CH:32][CH:33]=1
Reactant: ClCc1coc(/C=C/c2ccc(Cl)cc2)n1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Cl)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a solution of 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (130 mg) in DMF (4 ml), 60% oily sodium hydride (22 mg) was added under ice cooling. After stirring at room temperature for 30 minutes, (E)-4-chloromethyl-2-[2-(4-chlorophenyl)ethenyl]oxazole (140 mg) was added under ice cooling. After stirring at 0° C. for 1 hour, then at room temperature overnight, water was added under ice cooling. The precipitate was collected by filtration, washed with water, and dissolved in a mixture of THF-ethyl acetate. This solution was dried over magnesium sulfate, after which it was concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate-diethyl ether to yield the titled compound (168 mg) as colorless crystals.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[N:19]=[C:18](S(C)(=O)=O)[N:17]=[C:16]2[NH:24][N:25]=[CH:26][C:15]=12)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH:27]([O:30][C:31]1[CH:37]=[C:36]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[C:35]([CH3:44])=[CH:34][C:32]=1[NH2:33])([CH3:29])[CH3:28].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:27]([O:30][C:31]1[CH:37]=[C:36]([CH:38]2[CH2:39][CH2:40][NH:41][CH2:42][CH2:43]2)[C:35]([CH3:44])=[CH:34][C:32]=1[NH:33][C:18]1[N:17]=[C:16]2[NH:24][N:25]=[CH:26][C:15]2=[C:14]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[N:19]=1)([CH3:29])[CH3:28]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(S(C)(=O)=O)nc2[nH]ncc12
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3cn[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a suspension of N-(2-(isopropylsulfonyl)phenyl)-6-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 mmol) in 1 mL of isopropanol, was added 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (0.5 mmol) and 4-methylbenzenesulfonic acid (0.5 mmol). The suspension was stirred at 150° C. for 3 hours. After prep-HPLC, the final product was obtained. 1H NMR (CDCl3, 400 MHz) δ 8.74-8.77 (d, 1H), 8.24 (s, 1H), 7.92-7.96 (m, 2H), 7.65-7.70 (m, 1H), 7.27-7.33(m, 1H), 6.85(s, 1H), 4.60-4.67 (m. 1H), 3.71-3.74 (m, 2H), 3.25-3.32 (m, 1H), 2.78-2.97(m, 6H), 2.28-2.33 (m, 5H), 1.95-1.98 (m, 2H), 1.39-1.41(d, 6H), 1.33-1.35 (d, 6H); MS (ES+): 578.28 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][C:21]([OH:23])=O.C(OCC)(=O)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.C(N(CC)CC)C>[CH3:30][S:31]([O:23][CH2:21][CH2:20][CH2:19][C:4]1[C:5]([O:15][CH2:16][O:17][CH3:18])=[C:6]([O:13][CH3:14])[CH:7]=[C:8]([O:9][CH2:10][O:11][CH3:12])[C:3]=1[O:2][CH3:1])(=[O:33])=[O:32]
Reactant: COCOc1cc(OC)c(OCOC)c(CCC(=O)O)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCOc1cc(OC)c(OCOC)c(CCCOS(C)(=O)=O)c1OC
Reaction time: 12 h

Procedure:
700 Milligrams of 3-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]propionyl alcohol was dissolved in 20 ml of anhydrous methylene chloride, under argon gas stream condition, 0.21 ml of methanesulfonyl chloride, 0.3 ml of triethylamine were added thereto under ice-cooled condition. The temperature of the reaction mixture was elevated to room temperature, then the reaction mixture was stirred continuously for 12 hours. 100 Milliliters of ethyl acetate was added to the reaction mixture, and the organic layer was washed with water, a saturated sodium chloride aqueous solution, then concentrated to yield 700 mg of 3-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]propyl methanesulfonate was obtained as a mesylate. Colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][N:22]1[C:26]([C:27](O)=[O:28])=[CH:25][C:24]([CH3:30])=[N:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:26]3[N:22]([CH3:21])[N:23]=[C:24]([CH3:30])[CH:25]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1cc(C(=O)O)n(C)n1
Product: Cc1cc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)n(C)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 1,3-dimethyl-1H-pyrazole-5-carboxylic acid as starting materials, MS (LC/MS): 425.6 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[F:59][C:60]1[CH:65]=[CH:64][C:63]([CH2:66][CH2:67][NH2:68])=[CH:62][CH:61]=1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:68][CH2:67][CH2:66][C:63]3[CH:64]=[CH:65][C:60]([F:59])=[CH:61][CH:62]=3)=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(F)cc1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C(NCCc1ccc(F)cc1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), EDCI (72.5 mg, 0.378 mmol), and 1-hydroxybenzotriazole (51.1 mg, 0.378 mmol) were dissolved in DCM (Volume: 3.0 ml). The reaction was stirred at room temperature for 10 minutes before Hunig's Base (0.066 ml, 0.378 mmol) and 2-(4-fluorophenyl)ethanamine (0.050 ml, 0.378 mmol) were added. The reaction was allowed to stir overnight at room temperature. The reaction was diluted with water and ethyl acetate. The organic phase was washed with 1N HCl, saturated sodium bicarbonate, and brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude material was triturated with ethyl acetate to obtain product as a white solid. (Yield: 111 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 7.84, 7.62, 7.54, 7.36-7.30, 7.26-7.17, 7.14-7.04, 6.71, 5.49, 4.58-3.71, 3.25, 2.91, 2.69, 2.37-2.29, 1.61, 1.36
Reaction SMILES: [CH2:1]([OH:7])[C@@H:2]([OH:6])[CH2:3][CH2:4][OH:5].O.[C:9]1(C)[CH:14]=CC(S(O)(=O)=O)=C[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[OH:5][CH2:4][CH2:3][C@H:2]1[CH2:1][O:7][C:9]([CH3:14])([CH3:10])[O:6]1
Reactant: OCC[C@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OC[C@H](CCO)O1
Temperature: 25 °C
Reaction time: 21 h
Yield: 6655.7 %

Procedure:
To a solution of (s)-1,2,4-butanetriol (0.842 g, 7.9 mmol) dissolved in acetone (12 ml) was added p-toluenesulfonic acid hydrate (20 mg) and the mixture was stirred for 21 hours at room temperature. Sodium carbonate (20 mg) was added to the mixture. After stirring for 1 hour, the mixture was filtered and condensed in vacuo to give (S)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (1.023 g, yield 88%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][C:17]=2[O:30]CC2C=CC=CC=2)=[C:14]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:13]2[S:44][C:45]([C:47]([O:49][CH3:50])=[O:48])=[CH:46][C:12]1=2)[C:2]1C=CC=CC=1.Br.C(O)(=[O:54])C>C(O)(=O)C>[C:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[OH:30])=[C:14]([CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)[C:13]2[S:44][C:45]([C:47]([O:49][CH3:50])=[O:48])=[CH:46][C:12]1=2)(=[O:54])[CH3:2]
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(OCc3ccccc3)cc1OCc1ccccc1)n2CCOCc1ccccc1
Reactant: CC(=O)O
Agent: Br
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(O)cc1O)n2CCOC(C)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
To a solution of methyl 4-(2-benzyloxyethyl)-5-(2,4-bisbenzyloxyphenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.21 g, 1.77 mmol) in acetic acid (3 ml) was added 25% hydrogen bromide-acetic acid solution (3 ml), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure and the residue was subjected to azeotropic evaporation with toluene (5 ml×2). The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-0:1) to give methyl 4-(2-acetoxyethyl)-6-cyclohexyl-5-(2,4-dihydroxyphenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (762 mg, yield 94%).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Cl:13][C:14]1[C:15]2[CH:22]=[CH:21][N:20]([C@H:23]3[C@@H:27]4[O:28][C:29]([CH3:32])([CH3:31])[O:30][C@@H:26]4[C@@H:25]([CH2:33][OH:34])[CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1.N1C=CC=CC=1.C(O)(C(F)(F)F)=O>CS(C)=O.CCOC(C)=O>[Cl:13][C:14]1[C:15]2[CH:22]=[CH:21][N:20]([C@H:23]3[C@@H:27]4[O:28][C:29]([CH3:31])([CH3:32])[O:30][C@@H:26]4[C@@H:25]([CH:33]=[O:34])[CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C=O)C[C@H]2n1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
EDC.HCl (1.17 g, 6.11 mmol) was added to a solution of [(3aR,4R,6R,6aS)-6-{4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2,2-dimethylhexahydrocyclopenta[d][1,3]dioxol-4-yl]methanol (0.66 g, 2.04 mmol) in anhydrous DMSO (11 ml) and stirred at RT. Pyridine (0.33 ml, 4.08 mmol) followed by TFA (0.15 ml, 2.04 mmol) were added to the reaction mixture and stirred at RT (the reaction mixture becomes a slightly yellow solution). The reaction monitored by LCMS. The reaction mixture becomes dark brown after 30 mins. After 1.5 hrs, a further aliquot of EDC.HCl (583 mg, 3.06 mmol) was added and allowed to stir for a further 1.5 hrs at RT. The reaction mixture was diluted with EtOAc (50 ml). This was washed with brine (2×50 ml), dried over Na2SO4 and evaporated in vacuo. The crude product was absorbed onto silica gel (3 ml) placed onto a silica column and purified eluting with EtOAc/heptanes (4/6) to yield a colorless oil (260 mg 40%); MS (ESI+) for C15H16ClN3O3 m/z 1 [M+H]+, 321.90; HPLC purity>95% (ret. time, 1.72 min). 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.28-1.46 (3H, m), 1.54-1.77 (3H, m), 2.27-2.97 (2H, m), 3.17 (1H, td, J=8.72, 4.34 Hz), 4.82-5.13 (2H, m), 5.13-5.39 (1H, m), 6.45-6.84 (1H, m), 7.03-7.26 (1H, m), 8.47-8.86 (1H, m), 9.86 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(N(CC)CC)C.[C:41]1([CH2:47][CH2:48][S:49][CH:50]([C:54](O)=[O:55])[C:51](O)=[O:52])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[K+].[Br-]>>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:20][C:51](=[O:52])[C:50]([S:49][CH2:48][CH2:47][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:54]([OH:55])[CH:19]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccccc1COc1ccc(C(C)=O)cc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1COc1ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using 2-[[(4-acetyl)phenoxy]methyl]benzoic acid methyl ester (2.0 g, 7.04 mmol), trimethylsilyltrifluoromethylsulfonate (1.57 g, 7.04 mmol), triethylamine (1.42 g, 14.08 mmol) and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.04 g, 3.52 mmol). m.p. 161°-162° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.78 (t, 2 H), 2.97 (t, 2 H), 3.81 (s, 3 H), 5.5 (s, 2 H), 6.69 (s, 1 H), 7.14 (m, 3 H), 7.25 (m, 4 H), 7.5 (m, 2 H), 7.78 (m, 2 H), 7.78 (d, 2 H), 7.94 (d, 1 H); IR (KBr) 3028, 2949, 2909, 2675, 1715, 1638, 1510, 1402, 1291, 1267, 1181, 1030, 828, 747 cm-1 ; MS (CI) m/e 489 (M+H, 51), 384 (3), 353 (1), 149 (100), 135 (47), 105 (33).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:8]=1[CH:15]=[O:16])(=O)=O.[CH2:19](C([SnH3])=C(CCCC)CCCC)[CH2:20]CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:15]([C:8]1[CH:9]=[CH:10][C:11]([C:13]#[N:14])=[CH:12][C:7]=1[CH:19]=[CH2:20])=[O:16]
Reactant: N#Cc1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=Cc1cc(C#N)ccc1C=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
125 mg (0.18 mmol) of bis(triphenylphosphine)palladium(II) chloride are added to a solution of 1 g (3.58 mmol) of 5-cyano-2-formylphenyl trifluoromethanesulfonate and 1.15 ml (3.94 mmol) of tri-n-butylvinylstannane in 6 ml of anhydrous and degassed DMF under an argon atmosphere. The reaction mixture is then stirred at 80° C. for 90 min. Subsequently, 100 ml of 10% strength potassium fluoride solution are added, and the mixture is stirred at RT for 1 h. The suspension is extracted three times with 20 ml of ethyl acetate each time, and the combined organic phases are washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic solution is dried over magnesium sulfate and concentrated. The residue (0.6 g) is employed without further purification in the next stage.
Reaction SMILES: Br[CH:2]([CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[OH:11])=[O:4].C(=O)(O)[O-].[Na+].[BH4-].[Na+]>CO>[CH2:16]([CH:2]1[CH:3]([OH:4])[C:5]2[CH:6]=[C:7]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][C:10]=2[O:11]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCC(Br)C(=O)c1cc(NC(C)=O)ccc1O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCC1Oc2ccc(NC(C)=O)cc2C1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
A mixture of N-[3-(2-bromohexanoyl)-4-hydroxyphenyl]acetamide [6a] (3.28 g, 10.0 mmol), sodium bicarbonate (0.84 g, 10.0 mmol) and methanol (30 mL) was stirred under reflux conditions for 2 hours. Sodium borohydride (0.76 g, 20.0 mmol) was added in several portions to the mixture at 0-5° C. (ice/water bath). The mixture was stirred for 1 hour at the same temperature. Methanol (20 mL) was evaporated from the mixture and water (100 mL) was added to the residue. The obtained mixture was stirred for 1 hour at 0-5° C. (ice/water bath). The precipitated crystals were filtered and dried under reduced pressure at 50-60° C. to give 2.01 g (80.6% yield from 2 steps) of N-(2-butyl-3-hydroxy-2,3-dihydro-5-benzofuranyl)acetamide [9a] as off-white crystals with mp 134-137° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[NH:9][N:8]=2)[N:6]=1.[NH2:15][C@@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:10]3[CH:11]=[C:7]([C:5]4[N:6]=[C:2]([CH3:1])[S:3][CH:4]=4)[NH:8][N:9]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: Cc1nc(-c2cc(C(=O)O)[nH]n2)cs1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: Cc1nc(-c2cc(C(=O)N[C@@H](C)Cn3ccc(-c4ccc(C#N)c(Cl)c4)n3)n[nH]2)cs1
Yield: 18 %

Procedure:
3-(2-Methylthiazol-4-yl)-1H-pyrazole-5-carboxylic acid (0.586 mmol) was coupled with (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile using the method of Example 34(d). Crude product was purified by CombiFlash (silica column, eluent: 50-100% EtOAc in heptane) to obtain 24 mg (18%) of the title compound 1H-NMR (400 MHz; CDCl3): δ 1.24 (d, 3H), 2.77 (s, 3H), 4.28 (dd, 1H), 4.44 (dd, 1H), 4.55-4.67 (m, 1H), 6.59 (d, 1H), 7.06 (s, 1H), 7.38 (s, 1H), 7.49 (d, 1H), 7.60 (d, 1H), 7.74 (dd, 1H), 7.82 (d, 1H), 8.06 (d, 1H), 11.75 (bs, 1H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.Br[CH2:32][CH2:33][CH2:34][C:35]#[N:36].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:32][CH2:33][CH2:34][C:35]#[N:36])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(O)cc1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OCCCC#N)cc1
Yield: 76.1 %

Procedure:
A mixture of the phenol prepared in example 91 (0.90 g, 2.2 mmol), 4-bromobutyronitrile (0.5 mL, 5.0 mmol), potassium carbonate (0.97 g, 7.0 mmol), potassium iodide (0.1 g) and methyl ethyl ketone (30 mL) was heated at reflux for 10 h. The reaction was concentrated in vacuo and the resulting residue partitioned between EtOAc and water. The layers were separated and the aqueous layer extracted with EtOAc (3×). The combined organic layers were washed with water (3×), brine, dried (MgSO4), and concentrated in vacuo to a light pink oil. The material was purified by flash chromatography over silica gel eluting with 5% MeOH/CHCl3 to provide 0.79 g (76%) of a clear oil. MS (FD+) 471.65. NMR.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]([O:17]CC)=[O:16])=[CH:9]2)([O-:5])=[O:4].[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH2:23]Cl.Cl>CS(C)=O.O>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH2:23][N:11]1[C:12]2[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=2)[CH:9]=[C:10]1[C:15]([OH:17])=[O:16]
Reactant: Fc1cccc(F)c1CCl
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2n1Cc1c(F)cccc1F
Reaction time: 0.5 h

Procedure:
Under an atmosphere of argon, 5.49 g (83.2 mmol, 85% pure) of potassium hydroxide (powder) are initially charged in 110 ml of dimethyl sulphoxide, 6.43 g (27.5 mmol) of ethyl 5-nitro-1H-indole-2-carboxylate (A. Guy, J.-P. Guetté, Synthesis 1980, 222–223) are added at RT and the mixture is stirred for 30 min. With ice-cooling, at an internal temperature of 5–10° C., 2,6-difluorobenzyl chloride (10.0 g, 61.5 mmol) is then added dropwise over a period of 15 min, and the mixture is stirred at RT for 16 h. For work-up, the mixture is poured into 500 ml of water and acidified with dil. hydrochloric acid and the precipitated solid is filtered off with suction and pre-purified chromatographically on silica gel 60 (mobile phase gradient dichloromethane→dichloromethane-methanol 3:1). The resulting product is recrystallized from ethanol. This gives 4.33 g (47% of theory) of a pale-yellow crystalline solid.
Reaction SMILES: [CH2:1]([S:3][C:4]([CH3:14])([CH3:13])[C:5]([CH2:7][C:8]([O:10]CC)=O)=[O:6])[CH3:2].[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:45])[CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=2[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])=[CH:19][C:17]=1[NH2:18]>C1(C)C(C)=CC=CC=1>[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:45])[CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=2[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])=[CH:19][C:17]=1[NH:18][C:8](=[O:10])[CH2:7][C:5](=[O:6])[C:4]([S:3][CH2:1][CH3:2])([CH3:13])[CH3:14]
Reactant: CCC(C)(C)c1ccc(OCCCC(=O)Nc2ccc(Cl)c(N)c2)c(C(C)(C)CC)c1
Reactant: CCOC(=O)CC(=O)C(C)(C)SCC
Solvent: Cc1ccccc1C
Product: CCSC(C)(C)C(=O)CC(=O)Nc1cc(NC(=O)CCCOc2ccc(C(C)(C)CC)cc2C(C)(C)CC)ccc1Cl
Yield: 87 %

Procedure:
A mixture of 21.8 g of ethyl (2-ethylthio-2-methylpropionyl)-acetate obtained in Step 1 of Synthesis Example 1, 44.5 g of 2-chloro-5-[4-(2,4-di-tert-amylphenoxy)butyramido]aniline and 500 ml of xylene was refluxed for ten hours. Xylene was distilled off from the reaction mixture, and the residue was recrystallized from acetonitrile to obtain 53 g (yield 87%) of Coupler (2) having a melting point of 121° to 122° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[Br:11]Br>C(O)(=O)C>[NH2:1][C:2]1[C:6]([Br:11])=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: BrBr
Reactant: COC(=O)c1sccc1N
Solvent: CC(=O)O
Product: COC(=O)c1scc(Br)c1N
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a solution of methyl 3-aminothiophene-2-carboxylate (1 g, 6.36 mmol) in acetic acid (10 mL) was added a solution of bromine (0.32 mL, 6.36 mmol) in acetic acid (1 mL) slowly for 5 min at rt and stirred at the same temperature for 16 h. The reaction mixture was poured into ice cold water and extracted with chloroform (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (95:5) as eluents to give the product as a pale yellow color solid (0.5 g, 33%), mp 58-60° C.