Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[S:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:29]2[CH:30]=[CH:31][S:27][CH:28]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CC1
Yield: 55.7 %

Procedure:
Following the general procedure of Example 65, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (100 mg, 0.24 mmols), 3-thienylboronic acid (92 mg, 0.72 mmols), potassium carbonate (197 mg), and Pd(PPh3)4 (28 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (57 mg, 55%)
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:37])[NH:5][C:6](=[O:36])[N:7]([CH:35]=1)[C@@H:8]1[O:34][C@H:12]([CH2:13][O:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>N1C=CC=CC=1>[CH2:1]([C:3]1[C:4](=[O:37])[NH:5][C:6](=[O:36])[N:7]([CH:35]=1)[C@@H:8]1[O:34][C@H:12]([CH2:13][O:14][C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:10]([O:11][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:9]1)[CH3:2]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 5-ethyl-5'-O-trityl-2'-deoxyuridine (7.5 g, 15 mmole) in dry pyridine (50 ml), methanesulfonyl chloride (4.0 g, 35 mmole) is added while cooling in an ice-water bath. The mixture is stirred for one hour at around 0° C. and followed by allowing the temperature to rise to room temperature. At this point, tlc indicates no remaining starting materials. The mixture is then poured into an ice-water mixture (1.5 liters) while stirring, the water is decanted, and the product is washed with cold water several times, dissolved in chloroform and dried (over MgSO4). Finally, the solvent is evacuated in vacuo to obtain a syrup (7.6 g, 90%). This material is sufficiently pure to carry out the next reaction without further purification. However, an analytical sample can be obtained by column chromatography or tlc using chloroform as an eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.O.[C:11]1([S:17]([CH2:20][C:21]#[N:22])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1CCCCC1>C1C=CC=CC=1.C(O)(=O)C>[C:2]1([CH3:1])[CH:9]=[CH:8][C:5]([CH:6]=[C:20]([C:21]#[N:22])[S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:18])=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: N#CCS(=O)(=O)c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: Cc1ccc(C=C(C#N)S(=O)(=O)c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 5 h

Procedure:
120 g (1 mole) of p-methylbenzaldehyde were heated to the boil on a water separator and under reflux with 181 g (1 mole) of phenylsulfonyl-acetonitrile in 500 ml benzene with addition of 6 ml of piperidine and 3 ml of glacial acetic acid. After 5 hours, 17 ml water had separated. Upon cooling to 10° C, the 1-p-tolyl-2-cyano-2-phenylsulfonyl-ethlene crystallized; after suction filtration, washing with 150 ml of cold benzene and drying, 206 g (73% of the theory) were obtained; melting point: 145°-147° C. ##STR14##
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[N:7]([C:10]2[S:11][C:12]([C:16]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:6]=[N:5]1.[H-].[Na+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1>O1CCCC1.C(OCC)(=O)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:1][CH2:2][CH2:3][N:4]2[C:8](=[O:9])[N:7]([C:10]3[S:11][C:12]([C:16]([NH:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[O:17])=[C:13]([CH3:15])[N:14]=3)[CH:6]=[N:5]2)=[CH:31][CH:32]=1
Reactant: Cc1nc(-n2cnn(CCO)c2=O)sc1C(=O)NCc1cccnc1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-n2cnn(CCOCc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To the solution of 2-(1-(2-hydroxyethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.11 g, 0.31 mmol) in anhydrous tetrahydrofuran was added sodium hydride (60% in mineral oil, 0.015 g, 0.35 mmol) at 0° C. The reaction mixture was stirred for 30 minutes, followed by the addition of 1-(bromomethyl)-4-fluorobenzene (0.04 mL, 0.31 mmol). The resulting mixture was stirred at ambient temperature for 17 hours, diluted with ethyl acetate and washed with water and brine. The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate to afford the title compound as a white solid in 46% yield (0.06 g): mp 235-236° C. (ethyl acetate): 1H NMR (300 MHz, DMSO-d6) δ 9.14 (br s, 1H), 9.11-9.06 (m, 1H), 8.95 (t, J=5.5 Hz, 1H), 8.73 (s, 1H), 8.56-8.48 (m, 1H), 8.15-8.08 (m, 1H), 7.65-7.56 (m, 2H), 7.32-7.22 (m, 2H), 5.81 (s, 2H), 4.57 (d, J=5.5 Hz, 2H), 3.79 (t, J=5.4 Hz, 2H), 3.64 (t, J=5.4 Hz, 2H), 2.54 (s, 3H): 13C NMR (75 MHz, DMSO-d6) δ 162.0, 161.4, 152.6, 152.1, 150.6, 145.1, 143.8, 143.7, 141.1, 131.9, 131.9, 131.0, 128.7, 121.9, 116.6, 62.9, 58.6, 48.3, 40.7, 17.5: MS (ES+) m/z 469.2 (M+1).
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)C=CC=CC=1.C1COCC1.C([Li])CCC.[CH3:45][C:46]1[CH:61]=[CH:60][C:49]([CH2:50][O:51][C:52]2[CH:53]=[C:54]([CH:57]=[CH:58][CH:59]=2)[CH:55]=O)=[CH:48][CH:47]=1>CCCCCC.O>[CH3:45][C:46]1[CH:61]=[CH:60][C:49]([CH2:50][O:51][C:52]2[CH:53]=[C:54]([CH:57]=[CH:58][CH:59]=2)/[CH:55]=[CH:9]/[C:10]2[CH:11]=[CH:12][C:13]([CH2:16][N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:14][CH:15]=2)=[CH:48][CH:47]=1
Reactant: c1ccc([P+](Cc2ccc(CN3CCCCC3)cc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(COc2cccc(C=O)c2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(COc2cccc(/C=C/c3ccc(CN4CCCCC4)cc3)c2)cc1
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a mixture comprising triphenyl[4-(piperidinomethyl)benzyl]phosphonium bromide (1.06 g) and THF (10 ml) was added dropwise under a nitrogen atmosphere a 1.6 M solution of butyllithium in hexane (1.28 ml), and the resulting mixture was stirred for 30 minutes. To this reaction mixture was added 3-(4-methylbenzyloxy)benzaldehyde (453 mg), and the resulting mixture was stirred at room temperature for one hour, was then mixed with water (100 ml) and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, was dried with anhydrous sodium sulfate and was then evaporated under reduced pressure to remove the solvent. The resulting residue was subjected to purification using column chromatography (ethyl acetate/triethylamine=20/1) and to recrystallization to obtain (E)-1-[4-[3-(4-methylbenzyloxy)styryl]benzyl]piperidine (compound 97) (330 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:22][NH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2]>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:8][C:7]2[C:2]([N:23]([CH3:22])[C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1
Reactant: CNc1cccnc1
Reactant: Clc1ncccc1CC(c1cccnc1)c1cccnc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CN(c1cccnc1)c1ncccc1CC(c1cccnc1)c1cccnc1
Temperature: 25 °C
Yield: 38 %

Procedure:
To a solution of 2-chloro-3-(2,2-dipyridin-3-ylethyl)pyridine (1.54 g) and 3-(methylamino)pyridine (732 mg) in 30 mL toluene were added tris(dibenzylideneacetone)-dipalladium(0) (119 mg), 1,1-bis(diphenylphosphino)ferrocene (144 mg), and sodium tert-butoxide (651 mg). The reaction was heated at 100 C under a stream of Ar for 5 h. The reaction was cooled to room temp, then partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The aqueous solution was extracted with CH2Cl2 (3×), and the combined organic solutions were dried (Na2SO4) and concentrated. Flash chromatography gave a dark semi-solid which was purified again by reverse phase HPLC to provide 727 mg of 3-(2,2-dipyridin-3-ylethyl)-N-methyl-N-pyridin-3-ylpyridin-2-amine. 1H NMR (500 MHz, CDCl3): δ 8.44 (m, 2H), 8.35-8.34 (m, 3H), 8.15 (d, J=4.2 Hz, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.42 (dd, J=7.6, 1.7 Hz, 1H), 7.36-7.34 (m, 2H), 7.19-7.12 (m, 3H), 7.03 (dd, J=7.6, 4.9 Hz), 6.96-6.94 (m, 1H), 4.26 (t, J=7.8 Hz, 1H), 3.25 (s, 3H), 3.16 (d, J=7.8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[C:10](O)(=O)[CH2:11][OH:12].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:10]([CH2:11][OH:12])=[N:9][N:8]=2)[N:3]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: O=C(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1nnc2ccc(Cl)nn12

Procedure:
A mixture of 3-chloro-6-hydrazinopyridazine (1.44 g, 9.96 mmol), glycolic acid (0.76 g, 10 mmol) and p-TsOH.H2O (2.37 g, 12.4 mmol) in toluene was refluxed overnight. Some oil formed at the bottom of the flask. LC-MS of this oil showed the desired product was formed. Toluene was decanted off, and the oil residue was suspended in water (10 mL), then basified with 3N aq. NaOH to pH=10, the resulting off-white solid was collected, and dried to give the title compound. LC-MS (ES+): 185/187 (3/1) [MH+]. 1H NMR (CDCl3): δ=2.96 (br s, 1H, —OH), 5.25 (s, 2H), 7.17 (d, J=9.6 Hz, 1H), 8.11 (d, J=9.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:10]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH3:18])=O)N)=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC[N:40](CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl.N>C1COCC1.CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:8]([C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[CH2:17][CH3:18])=[N:40][N:6]=2)[CH:7]=1
Reactant: CCN1CCC[C@H]1C(=O)N(N)c1ccc(F)cn1
Reactant: CCN(CC)CC
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN1CCC[C@H]1c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a solution of Intermediate 61a (190 mg, 0.75 mmol), Ph3P (395 mg, 1.51 mmol) and Et3N (419 μL, 3.01 mmol) in THF (6.00 mL) at 0° C. was added hexachloroethane (357 mg, 1.51 mmol). The reaction was stirred at RT overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (157 mg, 89%). LCMS (Method 2): Rt 0.28 min, m/z 235.2 [MH+].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][CH2:15]C(OCC)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2].C[CH2:36][O:37]CC>>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([CH:14]([CH3:15])[CH2:36][OH:37])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: CCOC(=O)CCC1=CCN(Cc2ccccc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Product: CC(CO)C1=CCN(Cc2ccccc2)CC1

Procedure:
1-benzyl-4-(1-ethoxycarbonyl)ethyl-1,2,3,6-tetrahydropyridine (18.0 g) in dry ether (70 cm3) was added dropwise at 0° to a stirred suspension of lithium aluminium hydride (2.7 g) in ether (70 cm3) over 0.5 hours. After 1 hour 1M sodium hydroxide (15 cm3) solution was added dropwise over 0.5 hours and after stirring for a further 1 hour magnesium sulphate (10 g) was added. The mixture was filtered, the filtrate evaporated in vacuo and the residue distilled to afford 1-benzyl-4-(1-hydroxyprop-2-yl)-1,2,3,6-tetrahydropyridine as an oil b.p. 200° 0.05 mm (Kugelrohr) (12.43 g).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[NH:16][CH:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1>O1CCCC1.O>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:31]([C:32]5[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=5)=[O:38])[CH2:20][CH2:19]4)[NH:16][CH:17]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc(-c3c[nH]c(C4CCNCC4)n3)cn2)cc1
Reactant: O=C(Cl)c1cccnc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1cccnc1)N1CCC(c2nc(-c3cnc(-c4ccccc4)nc3)c[nH]2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 2-phenyl-5-(2-(piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine (76 mg, 0.25 mmol) in tetrahydrofuran (4 mL) was added triethylamine (51 mg, 0.50 mmol) followed by nicotinoyl chloride (49 mg, 0.27 mmol) and the reaction mixture was stirred for 1 hour at 0° C. then allowed to warm to room temperature. The reaction was diluted with water and the organic material extracted three times with ethyl acetate. The combined organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude solid was chromatographed on silica (4 g) and eluted with ethanol-ethyl acetate to give the title compound as a solid; melting point 234° C.; Rf 0.31 with 0.5/10/40/50 acetic acid-isopropanol-hexane-dichloromethane; MS (ESI+) m/z 411 (M+1); H-PGDS FPBA IC50: 0.45 μM.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=1.[CH:24](N1CCCCC1)=[O:25]>O1CCCC1.CCCCCC.O.C(O)(=O)C>[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[C:15]=1[CH:24]=[O:25]
Reactant: O=CN1CCCCC1
Reactant: COc1cc(F)ccc1C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1c(C#N)ccc(F)c1C=O
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
Under nitrogen atmosphere and at −78° C., to a solution of 10.7 g of N,N-diisopropylamine in 150 mL of tetrahydrofuran was added 40 mL of 2.66 M n-butyllithium in n-hexane, stirred at this temperature for 1 hour and 15 minutes, and added dropwise with a solution of 14.5 g of 4-fluoro-2-methoxybenzonitrile obtained by Production example 95 in 50 mL of tetrahydrofuran. After stirring at this temperature for 2 hours, 11.94 g of N-formylpiperidine was added. After stirring at this temperature for 40 minutes, the solution was added with 20 mL of acetic acid at this temperature, added with water at room temperature, and extracted three times with diethyl ether. The organic layer was washed successively with 0.2N hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography, to afford 6.4 g of the title compound 6.4 g as pale yellow crystals.
Reaction SMILES: COC(C1SC([I:22])=C(C#N)C=1C1C=CC(C(C)(C)C)=CC=1)=O.[CH2:23]([O:25][C:26]([C:28]1[S:29][C:30](N)=[C:31]([C:47]#[N:48])[C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[S:45][CH3:46])=[CH:35][CH:34]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[S:29][C:30]([I:22])=[C:31]([C:47]#[N:48])[C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[S:45][CH3:46])=[CH:35][CH:34]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(-c2ccccc2SC)cc1
Reactant: COC(=O)c1sc(I)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Product: CCOC(=O)c1sc(I)c(C#N)c1-c1ccc(-c2ccccc2SC)cc1

Procedure:
Using a method substantially in accordance with the method of 3-(4-tert-butyl-phenyl-4-cyano-5-iodo-thiophene-2-carboxylic acid methyl ester starting with the compound 5-amino-4-cyano-3-(2′methylsulfanyl-biphenyl-4-yl)-thiophene-2-carboxylic acid ethyl ester gives the title compound: 1H NMR (400 MHz, CDCl3) δ 7.53-7.20 (m, 8H), 4.23 (q, 2H, J=7.2 Hz), 2.38 (s, 3H), 1.22 (t, 3H, J=7.0 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](N1C=CN=C1)=[S:8].Cl.[CH3:15][O:16][C:17](=[O:27])[CH:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19]>CN(C)C=O>[CH3:15][O:16][C:17](=[O:27])[CH:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:19][C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[S:8]
Reactant: COC(=O)C(N)Cc1ccccc1
Reactant: S=C(Nc1nccs1)n1ccnc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)NC(=S)Nc1nccs1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
A solution of 1-[(2-thiazolyl) thiocarbamoyl] imidazole (4.21 g, 20.0 mmol) and DL-phenylalanine methyl ester hydrochloride (4.31 g, 20.0 mmol) in N,N-dimethylformamide (150 mL) was heated at 90° C. for 3 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystallized from ether-hexanes to provide 3.26 g (51%) of the titled product:
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])=[CH:4][C:5]([C:8]2[C:13]3[O:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:22](B(O)O)[CH:23]([CH3:25])[CH3:24].O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH:11]1[C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:8]([C:5]2[CH:4]=[C:3]([CH3:21])[C:2]([CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: CC(C)CB(O)O
Reactant: Cc1cc(-c2cccc3c2oc2ccccc23)ncc1Br
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(-c2cccc3c2oc2ccccc23)ncc1CC(C)C
Temperature: 25 °C
Yield: 74.5 %

Procedure:
5-Bromo-2-(dibenzo[b,d]furan-4-yl)-4-methylpyridine (13.0 g, 38.3 mmol), isobutylboronic acid (11.7 g, 115 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.63 g, 1.53 mmol) and potassium phosphate monohydrate (22.1 g, 96 mmol) were mixed in water (10 mL) and toluene (210 mL). The system was degassed for 20 min. with nitrogen and Pd2(dba)3 (0.35 g, 0.38 mmol) was then added and the system was refluxed overnight. After cooling to room temperature, the reaction mixture was filtered through a small plug of silica gel and eluted with dicloromethane. The filtrated was concentrated and then crystallized from hexane to give 2-(dibenzo[b,d]furan-4-yl)-5-isobutyl-4-methylpyridine (9.0 g, 74%).
Reaction SMILES: [CH:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:2]([CH:1]1[O:18][CH2:17][CH2:16][O:15]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OCCO
Reactant: CCCCC/C=C\CCCCCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC/C=C\CCCCCCC1OCCO1
Reaction time: 3 h

Procedure:
5.6 g (Z)-8-tetradecenal (6), 2.0 g ethylene glycol and 20 mg p-toluenesulphonic acid in 150 ml toluene were boiled in a water separator for 3 h. The reaction mixture was washed with sodium bisulphate solution and dried over sodium sulphate and the solvent was distilled off. Chromatography on silica gel gave 2-[(Z)-tridec-7-enyl]-1,3-dioxolane (7).
Reaction SMILES: O/[C:2](=[C:8]1/[CH2:9][O:10][CH2:11][CH2:12][C:13]/1=O)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[NH2:16][NH2:17]>CO>[N:16]1[NH:17][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]2[CH2:9][O:10][CH2:11][CH2:12][C:13]=12
Reactant: NN
Reactant: CCOC(=O)/C(O)=C1\COCCC1=O
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1[nH]nc2c1COCC2
Temperature: 25 °C

Procedure:
(Z)-ethyl 2-hydroxy-2-(4-oxo-2H-pyran-3(4H, 5H, 6H)-ylidene)acetate (2.5 g, 12.49 mmol) was dissolved in methanol (10 ml). Hydrazine hydrochloride (2.57 g, 37.5 mmol) was added and the resulting mixture was refluxed for one hour. The mixture was allowed to warm to RT and the solvent was evaporated. The residue was dissolved in DCM and extracted twice with water. The organic layer was dried with Na2SO4, filtered and evaporated. The product was purified with flash chromatography. 1H-NMR (400 MHz; d6-DMSO): δ 1.27 (d, 3H), 2.70 (t, 2H), 3.81 (t, 2H), 4.24 (q, 2H), 4.69 (s, 2H), 13.40 (bs, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH:14]([OH:15])[CH2:13][C@@H:12]([CH:16]2[CH2:18][CH2:17]2)[N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]1[C:14](=[O:15])[CH2:13][C@@H:12]([CH:16]2[CH2:17][CH2:18]2)[N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(CO[Si](C)(C)C(C)(C)C)C(O)C[C@H]1C1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(CO[Si](C)(C)C(C)(C)C)C(=O)C[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
(5S)-tert-Butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-cyclopropyl-3-hydroxypyrrolidine-1-carboxylate (33) (2.72 g, 7.32 mmol) was dissolved in CH2Cl2 (35 mL). NaHCO3 (2.76 g, 32.9 mmol) and Dess-Martin periodinane (4.65 g, 10.98 mmol) were added and the resulting suspension was stirred at rt for 2 h. A mixture of sat. aq. NaHCO3 and sat. aq. sodium sulfite (20 mL, 1/1) was added and the resulting solution was stirred for 15 minutes. The biphasic mixture was extracted with CH2Cl2 (30 mL) and the organic phase was dried (Na2SO4), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/EtOAc, 9/1 to 1/1 to give 1.54 g (56%, 3 steps) of (5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-cyclopropyl-3-oxopyrrolidine-1-carboxylate (34). Retention time (min)=2.628, method [2], MS (m/z) 392.2 (M+Na)+.