Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[N:12][N:13]([CH2:15][CH2:16][C@@:17]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([O:20]CC)=[O:19])[CH:14]=1.[OH-].[Li+].Cl>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[N:12][N:13]([CH2:15][CH2:16][C@@:17]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([OH:20])=[O:19])[CH:14]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(-c2nc3ccccc3o2)cn1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@](CCn1cc(-c2nc3ccccc3o2)cn1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of ethyl (2R)-4-[4-(1,3-benzoxazol-2-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoate (0.482 g, 1.23 mmol) in THF/H2O (20 mL:10 mL) was added lithium hydroxide (0.295 g, 12.3 mmol, 10 eq). The mixture was allowed to stir at RT overnight. The mixture was acidified with 1M HCl and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to give (2R)-4-[4-(1,3-benzoxazol-2-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (0.420 g, 94% yield) as a white solid. LC-MS M+H+364.1.
Reaction SMILES: [H-].[Li+].[F:3][C:4]([F:17])([F:16])[C:5]([C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[C:9]([Cl:15])[CH:8]=1)=[O:6].[CH3:18][O:19][C:20]([C:22]1[CH:26]=[C:25]([C:27](=[O:29])[CH3:28])[O:24][C:23]=1[CH3:30])=[O:21].CC(OC)(C)C>C1COCC1>[CH3:18][O:19][C:20]([C:22]1[CH:26]=[C:25]([C:27](=[O:29])[CH2:28][C:5]([OH:6])([C:7]2[CH:8]=[C:9]([Cl:15])[C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=2)[C:4]([F:3])([F:16])[F:17])[O:24][C:23]=1[CH3:30])=[O:21]
Reactant: O=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1cc(C(C)=O)oc1C
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)CC(O)(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)oc1C
Reaction time: 1 h
Yield: 123.5 %

Procedure:
LiH (1.76 g) is added to a solution of 2,2,2-trifluoro-1-(3,4,5-trichloro-phenyl)-ethanone (35.33 g) and 5-acetyl-2-methyl-furan-3-carboxylic acid methyl ester (20 g) in THF (300 ml). After 1 hour 30 at 60° C. MTBE is added (450 ml) and the reaction mixture is poured onto water (750 ml) at 0° C. The organic phase is washed with water and a saturated aqueous solution of NaCl dried over MgSO4 and concentrated in vacuo to yield 62.3 g of 2-methyl-5-[4,4,4-trifluoro-3-hydroxy-3-(3,4,5-trichloro-phenyl)-butyryl]-furan-3-carboxylic acid methyl ester. The crude product is used without further purification. MS (HPLC/MS): 459 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.CN(C)C=O.[H-].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CO.O1CCCC1>[CH2:34]([O:15][C:10]1[CH:11]=[C:12]2[C:7]3=[C:8]([C:16](=[O:26])[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][N:6]3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]2=3)[CH:9]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(OCc4ccccc4)cc1c32
Temperature: 25 °C
Reaction time: 12 h
Yield: 146.7 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (2.0 g) obtained in Example 2 was suspended in a mixed solvent of anhydrous dimethylformamide (64 ml) and anhydrous tetrahydrofuran (120 ml), and sodium hydride(60%, 260 mg) was added to the suspension in an ice bath. Benzylbromide (400 mg) was added dropwise and the mixture was stirred at room temperature for 12 hours. A small amount of methanol was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N aqueous solution of sodium hydroxide and saturated aqueous solution of sodium chloride in succession, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride containing 3% methanol) to produce the title compound (1.7 g, 67%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[CH2:11]([O:13][C:14]([C:16]1[C:17](=[O:39])[C:18]2[CH:23]=[N:22][C:21](S(C)(=O)=O)=[N:20][C:19]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1[C:17](=[O:39])[C:18]2[CH:23]=[N:22][C:21]([NH:1][CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][C:6]3=[O:10])=[N:20][C:19]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=[O:15])[CH3:12]
Reactant: NCCCN1CCCC1=O
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCN3CCCC3=O)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1 Step F, the title compound was prepared from 1-(3-amino-propyl)-pyrrolidin-2-one and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(Step E) 25 mg, 0.052 mmol). 17 mg of 8-Indan-5-yl-5-oxo-2-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.25 (s, 1H), 8.46 (s, 1H), 7.33 (d, J=7.7 Hz, 1H), 7.23 (s, 1H), 7.16 (d, J=7.7 Hz, 1H), 6.26 (br, 1H), 4.37 (q, J=7.3 Hz, 2H), 3.36 (m, 2H), 3.27 (m, 2H), 3.00 (m, 4H), 2.37 (t, J=7.9 Hz, 2H), 2.18 (m, 2H), 2.00 (m, 2H), 1.60 (m, 4H), 1.38 (t, J=7.3 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[S:5].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[CH:13]1([CH2:12][O:1][C:2]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=2[CH:4]=[S:5])[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: Cc1ccc(O)c(C=S)c1
Product: Cc1ccc(OCC2CC2)c(C=S)c1

Procedure:
2-Hydroxy-5-methylthiobenzaldehyde was alkylated with bromomethylcyclopropane using a similar method to that of reference example 4 to give 2-cyclopropylmethoxy-5-methylthiobenzaldehyde.
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([F:31])[N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)Cl>[CH2:1]([S:3]([CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([F:31])[N:10]([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)=[O:40])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Solvent: ClCCl
Product: CCS(=O)CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 0.17 h

Procedure:
A solution of ethanethiol in DMF was treated with sodium hydride, and then with 2-fluoro-4-(3-methanesulphonyloxypropyl)-1-triphenylmethylimidazole. After stirring at ambient temperature for 16 hours, the mixture was worked up by extraction and chromatography to give 4-(3-ethylthiopropyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.2 (t, 3H); 1.85 (quintet, 2H); 2.48 (q, 6H); 6.24 (s, 1H); 7.0-7.4 (m, 15H). This thioether was dissolved in CH2Cl2, cooled to 0°, and treated in portions with one equivalent of 3-chloroperbenzoic acid, having the reaction closely by HPLC. Complete conversion to product occurred 10 minutes after the final addition of peracid. The solution was extracted with aqueous sodium bicarbonate, dried and evaporated to give 4-(3-ethanesulphinylpropyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.28 (t, 3H); 2.02 (quintet, 2H); 2.66 (m, 6H); 6.27 (s, 1H); 7.0-7.4 (m, 15H).
Reaction SMILES: C([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9])=O.C1(C)C=CC(S([N:19]=[N+:20]=[N-])(=O)=O)=CC=1>>[N+:19](=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9])=[N-:20]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=CC1CCCCC1=O
Product: [N-]=[N+]=C1CCCCC1=O

Procedure:
Reaction of a formyl cyclohexanone derivative with para-toluenesulfonylazide effects displacement of the formyl group by a diazo moiety to provide a diazocyclohexanone derivative. For example, a formyl cyclohexanone derivative such as 2-phenyl-2-(2-cyanoethyl)-6-formylcyclohexanone can be reacted with about an equimolar quantity of para-toluene-sulfonylazide in the presence of dimethylamine or diethylamine, in an organic solvent such as diethyl ether, to provide, for instance, 2-phenyl-2-(2-cyanoethyl)-6-diazocyclohexanone.
Reaction SMILES: C([N:4]1[C:12]2[CH:7]([N:8](C(=O)C)[CH2:9][N:10](C(=O)C)[C:11]=2Cl)[N:6]([C@@H:20]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]2[OH:22])[CH2:5]1)(=O)C.[CH3:29][NH:30][CH2:31][CH:32]=[CH:33][CH3:34].C(N(CC)CC)C>C(O)(C)C>[CH3:29][N:30]([CH2:31][CH:32]=[CH:33][CH3:34])[C:11]1[C:12]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:20]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]1[OH:22]
Reactant: CC(=O)N1CN(C(C)=O)C2C(=C1Cl)N(C(C)=O)CN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC=CCNC
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC=CCN(C)c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 8 h
Yield: 70 %

Procedure:
7.3 g. triacetyl-6-chloro-9-(β-D-ribofuranosyl)-purine, 2.1 g. methyl-but-2-enylamine and 2.8 ml. triethylamine were heated under reflux for 2 hours in 100 ml. isopropanol. After cooling, the reaction mixture was mixed with 200 ml. diethyl ether, extracted twice with water and the organic phase evaporated to dryness in a vacuum. The residue was dissolved in 100 ml. 25% methanolic ammonia and then left to stand overnight at ambient temperature. The solution was thereafter evaporated and the residue obtained was recrystallized from water. 4.1 g. (70% of theory) N(6)-methyl-N(6)-but-2-enyl-adenosine were obtained; m.p. 160° - 162° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH2:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:27][CH:26]=1)[CH3:24]
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cncnc1
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2cc(NC(=O)c3cncnc3)cnc2OCC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to Example 39, using pyrimidine-5-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 52 a) and B-(4-ethylphenyl)-boronic acid (CAN 63139-21-9) as starting materials; LC-MS (UV peak area/ESI) 100%, 403.1384 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.[O:23]1CCO[CH:24]1[C:28]1[C:33]([CH3:34])=[CH:32][C:31]([NH:35][C:36](=[O:39])[CH:37]=[CH2:38])=[C:30]([CH3:40])[CH:29]=1.C(O)C.[ClH:44]>ClCCl>[ClH:44].[CH:24]([C:28]1[C:33]([CH3:34])=[CH:32][C:31]([NH:35][C:36]([CH2:37][CH2:38][N:1]2[CH2:2][CH2:3][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:5][CH2:6]2)=[O:39])=[C:30]([CH3:40])[CH:29]=1)=[O:23]
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Reactant: C=CC(=O)Nc1cc(C)c(C2OCCO2)cc1C
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 50 mL round-bottom flask was added biphenyl-2-ylcarbamic acid piperidin-4-yl ester (1.2 g, 4.04 mmol) and N-(4-[1,3]dioxolan-2-yl-2,5-dimethylphenyl)acrylamide (1.0 g, 4.04 mmol). Ethanol (10 mL) and dichloromethane (10 mL) were added to form a slurry. The reaction mixture was heated at 45° C. to 50° C. for about 18 hours and then cooled to room temperature. Aqueous 1M hydrochloric acid (10 mL) was added and the resulting mixture was stirred vigorously for about 3 hours. Dichloromethane (10 mL) was added and the resulting mixture was stirred for about 5 minutes. The layers were then separated and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to provide crude biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester hydrochloride (1.9 g). 1H NMR (300 MHz, DMSO-d6) δ 1.2-1.4 (m, 2H), 1.58-1.75 (m, 2H), 2.0-2.17 (m, 2H), 2.19 (s, 3H), 2.38 (s, 3H), 2.41-2.50 (m, 4H), 2.5-2.75 (m, 2H), 4.31-4.42 (m, 1H), 7.10-7.35 (m, 9H), 7.55 (s, 1H), 7.75 (s, 1H), 8.59 (s, 1H), 9.82 (s, 1H), 9.98 (s, 1H); MS [M+H+] found 500.2.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([S:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)=[C:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[S:11][C:5]=2[N:4]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:3]1=[O:37].[Cl-].[NH4+].[OH-].[Na+]>C(O)C.O.[Fe]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([S:23][C:9]2[C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:37])[N:4]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:5]=3[S:11][C:10]=2[CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)=[CH:25][CH:26]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3ccc([N+](=O)[O-])cc3)c(Cc3cccc4ccccc34)sc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3ccc(N)cc3)c(Cc3cccc4ccccc34)sc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.5 %

Procedure:
A suspension of the crude 3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(4-nitrophenyl)thio]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione (Example 35, 1.26 g), iron powder (0.59 g) and ammonium chloride (0.56 g) in ethanol (5 ml) and water (5 ml) was heated at reflux for 4 hours, then cooled to room temperature. Sodium hydroxide solution (10%, 50 ml) was added and the mixture was stirred for 1 hour. The resulting solution was decanted from insoluble solid. The solid and solution were in turn extracted with dichloromethane (3×50 ml) then ethyl acetate (3×50 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was partially purified by column chromatography over silica, eluting with ethyl acetate:isohexane (1:1). Some pure material was recrystallised from isohexane:ethyl acetate to give the title compound (0.065 g). The remaining material was purified by preparative normal-phase HPLC with dichloromethane:ethanol gradient elution to give the title compound (0.163 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]([F:13])([F:12])C([O-])=O.[Na+].CN(C=O)C.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][N:22]=1>CCOCC>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:8]([F:12])[F:13])=[CH:23][N:22]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(Br)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
Potassium carbonate (2.4 g, 17.3 mmols) and sodium chlorodifluoroacetate (4.2 g, 27.5 mmols) were added to a DMF (20 mL) solution of 2-bromo-5-hydroxypyridine (2.4 g, 13.8 mmols) and stirred overnight at 80° C. The reaction liquid was cooled to room temperature, added ether, washed with water and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the resulting residue was purified on silica gel column chromatography (C-300; hexane:ethyl acetate=100:1-100:2) to provide the title compound (1.32 g, 43%).
Reaction SMILES: [CH3:1][C:2]#[N:3].[H-].[Na+].[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:25](OC)=[O:26])=[CH:13][C:14]=1[O:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[CH3:17])=[O:9]>O1CCOCC1>[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:25](=[O:26])[CH2:1][C:2]#[N:3])=[CH:13][C:14]=1[O:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[CH3:17])=[O:9]
Reactant: CC#N
Reactant: COC(=O)c1cc(OC(C)c2ccccc2Cl)c(C(=O)OC)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1sc(C(=O)CC#N)cc1OC(C)c1ccccc1Cl
Temperature: 25 °C
Yield: 5.7 %

Procedure:
MeCN (231 mg, 5.62 mmol, 1.0 Eq.) was added to a suspension of NaH (225 mg, 60% dispersion in mineral oil, 5.62 mmol, 1.0 Eq.) in anhydrous dioxane (30 mL) at ambient temperature under nitrogen. After stirring for 25 minutes 3-[1-(2-Chlorophenyl)-ethoxy]-thiophene-2,5-dicarboxylic acid dimethyl ester (1.94 g, 5.62 mmol, 1.0 Eq.) was added and the reaction heated at reflux overnight. The reaction was cooled to ambient temperature, quenched with water and partitioned between EtOAc (100 mL) and brine (100 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and the combined organic extracts dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (50% EtOAc/Petroleum ether) to give the sub-title compound as a white solid (115 mg, 0.32 mmol, 6%); 1H NMR (400 MHz, d-6 DMSO) δ 1.61 (3H, d), 3.82 (3H, s), 4.62-4.74 (2H, m). 5.88 (1H, q), 7.35 (1H, t), 7.40 (1H, t), 7.48 (1H, d), 7.73 (1H, d), 7.91 (1H, s).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([O:32][CH3:31])[CH:38]=1)[CH3:2]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: COc1cccc(B(O)O)c1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2cccc(OC)c2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 3-methoxyphenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CDCl3) δ 10.14 (s,.1H); 7.45 (m, 2H); 7.36-7.41 (m, 4H); 7.02 (m 2H); 6.96 (m, 2H); 5.39 (s, 2H); 3.85 (s, 3H); 2.85 (q, J=7.3 Hz, 2H); 1.21 (t, J=7.3 Hz, 3H). HRMS (ES) exact mass calculated for C22H22NO4 (M+H): 364.1594. Found 364.1573
Reaction SMILES: [C:1]([NH:4][C:5]([CH:26]1[CH2:31][CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28][CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].C(OCC)(=O)C>CO.CCCCCCC.[Pd]>[C:1]([NH:4][C:5]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:18][C:19]([CH3:24])([CH3:25])[C:20]([CH3:23])([CH3:22])[O:21]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCNCC1
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
In a 100 mL round bottom flask while under an argon atmosphere, benzyl 4-(2-acetamido-1-(tert-butylamino)-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexan-2-yl)piperidine-1-carboxylate (3.0 g, 5.25 mmol) in methanol (40 mL) was degassed with argon (bubbled through solution) and subsequently treated with palladium (25 mg, 10 wt % on active carbon, wet, Degussa type E101 NE/W). After continued bubbling for 10 min the argon was replaced with a slow stream of hydrogen. After 1.5 h the reaction was complete (reaction monitored by TLC for the disappearance of starting material (50% ethyl acetate in heptane, Rf 0.3) and solution was purged with argon, filtered through the Celite 545 and the filter cake washed with methanol. The methanol solution was concentrated and collected solvents evaporated to give crude 2-acetamido-N-tert-butyl-2-(piperidin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (2.20 g 96%) which was used without further purification (contained approximately 10% product with loss of boronic acid protecting group). 1H NMR (CDCl3, 300 MHz) δ 6.95 (s, 1H), 5.53 (s, 1H), 3.09 (bt, J=11.1 Hz, 2H), 2.80 (ddd, J1=14.1 Hz, J2=13.5 Hz, J3=4.5 Hz, 1H), 2.65-2.48 (m, 2H), 2.26 (dddd, J1=12.0 Hz, J2=12.0 Hz, J3=3.0 Hz, J4=2.7 Hz, 1H), 2.00-1.90 (m, 1H), 1.98 (s, 3H), 1.78-1.63 (m, 2H), 1.45-1.00 (m, 5H), 1.36 (s, 9H), 1.21 (s, 8H), 0.73 (t, J=7.5 Hz, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH2:26]C=C)[CH2:23][CH:24]=[CH2:25])[N:16]=3)=[C:9]([F:35])[CH:8]=1.O>C(Cl)Cl.CC1C=C(C)C(N2[CH-]N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:23][CH:24]=[CH:25][CH2:26]2)[N:16]=3)=[C:9]([F:35])[CH:8]=1
Reactant: C=CCC(CC=C)(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1cc(C)c(N2[CH-]N(c3c(C)cc(C)cc3C)CC2)c(C)c1
Solvent: ClCCl
Solvent: O
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccc4)CC=CC3)nc2s1
Reaction time: 5 h

Procedure:
To a solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(4-phenylhepta-1,6-dien-4-yl)thiazolo[5,4-b]pyridine (1.07 g, 2.20 mmol) in 44 mL DCM under argon was added tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium(IV) dichloride (93.3 mg, 0.110 mmol). The reaction mixture became red-brown and was fitted with a water-cooled reflux condenser and heated to reflux. After 5 h, the reaction mixture was cooled, concentrated in vacuo, loaded onto an 80 g ISCO silica gel column, and purified with a gradient of 0-30% EA/hexanes to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylcyclopent-3-enyl)thiazolo[5,4-b]pyridine as an off-white solid. MS (ESI) m/z: Calculated: 458.2; Observed: 459.1 (M++1).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[ClH:12]>C1(C)C=CC=CC=1>[CH2:1]([Cl:12])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: Cl
Reactant: OCc1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Product: ClCc1ccc2c(c1)OCO2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
In a 500-ml flask were placed 30 g (0.2 mol) of piperonyl alcohol, 102.8 g (1.0 mol) of a 35% aqueous hydrochloric acid solution and 150 ml of toluene. They were stirred in a nitrogen stream at 90° C. for about 2 hours. The stirring was stopped and phase separation was made to remove the aqueous phase. The toluene phase was washed with water and an aqueous NaHCO3 solution in this order, and then with water several times. The toluene phase was concentrated under reduced pressure to obtain 32.28 g of piperonyl chloride. In a 500-ml flask were placed 8.4 g (0.21 mol) of sodium hydride and 100 ml of toluene, and they were stirred under refluxing in a nitrogen stream, in a 120° C. oil bath. Thereto was dropwise added, in 20 minutes, 29.6 g (0.19 mol) of 1-menthol dissolved in 30 ml of toluene. 30 minutes later, 32.3 g (0.19 mol) of the piperonyl chloride dissolved in 32 ml of toluene was added dropwise, followed by stirring for about 1 hour. The stirring was stopped and 110 ml of a 2 N aqueous hydrochloric acid solution was added to terminate a reaction, after which phase separation was made. The toluene phase was washed with water three times and then concentrated. The resulting concentrate was distilled for purification to obtain 35.6 g (yield: 30.6%, purity: 97.2%) of piperonyl 1-mentyl ether as a transparent oily substance.