Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15](OCC)=[O:16])=[C:13]([C:20]([F:23])([F:22])[F:21])[S:12][N:11]=2)=[CH:6][CH:5]=1)[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[F:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([C:20]([F:23])([F:22])[F:21])[S:12][N:11]=2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CCOC(=O)c1c(-c2ccc(C(C)F)cc2)nsc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(F)c1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
Into a 8-mL vial, was placed ethyl 3-[4-(1-fluoroethyl)phenyl]-5-(trifluoromethyl)-1,2-thiazole-4-carboxylate (290 mg, 0.83 mmol, 1.00 equiv), tetrahydrofuran (1 mL). This was followed by the addition of LiAlH4 (0.83 mL) dropwise with stirring at 0° C. in 1 min. The resulting solution was stirred for 1 h at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 1 mL of water. The resulting solution was extracted with 3×3 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 72 mg (28%) of [3-[4-(1-fluoroethyl)phenyl]-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol as a white solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4](Cl)=[C:5]2[C:11]=1[C:10](=[O:12])[C:9]1=[CH:13][S:14][CH:15]=[C:8]1[C:7](=[O:16])[NH:6]2.C([O-])=O.[NH4+].C(O)CC>[Pd].O>[CH:2]1[S:3][CH:4]=[C:5]2[C:11]=1[C:10](=[O:12])[C:9]1=[CH:13][S:14][CH:15]=[C:8]1[C:7](=[O:16])[NH:6]2
Reactant: O=c1[nH]c2c(Cl)sc(Cl)c2c(=O)c2cscc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCCO
Product: O=c1[nH]c2cscc2c(=O)c2cscc12
Temperature: 100 °C
Yield: 83 %

Procedure:
A mixture of 125 g (0.411 mole) of 1,3-dichloro-4,5-dihydrodithieno[3,4-b:3',4'-e]azepine-5,9-dione, 125 g (1.982 moles) of ammonium formate, 50 g of 5% strength Pd/C, 50 g of active carbon, 3.125 l of propanol and 165 ml of water was refluxed for 3 hours, while stirring, after which 2.5 l of solvent were distilled off under about 100 mbar, while stirring. The residue was poured onto 3 l of ice water, and the resulting suspension was acidified with concentrated hydrochloric acid, while stirring. Stirring was continued for a further hour, after which the mixture was filtered under suction and the residue was added to 1.8 l of dimethylformamide. The stirred mixture was heated at 100° C. and then filtered again under suction. The residue (Pd/C and active carbon) was washed with 5 times 100 ml of hot dimethylformamide. The original dimethylformamide mother liquor was combined with the dimethylformamide used for washing, and the still warm combined solutions were poured onto 9 l of cold water, while stirring. The precipitate formed during this procedure was filtered off under suction, washed with water and dried at 50° C., in a drying oven under reduced pressure. 80.6 g (83% OF 4,5-dihydrodithieno[3,4-b:3',4'-e]azepine-5,9-dione were obtained in the form of beige crystals of melting point 268.5°-271° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([O:28][CH2:29]C)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16]S(C3C(C)=NN(C)C=3Cl)(=O)=O)[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:31]OC1C=CC(C)=CC=1B(O)O.BrC1C=CC([C@H](N)C)=CC=1>>[CH3:29][O:28][C:5]1[CH:4]=[CH:3][C:2]([CH3:31])=[CH:7][C:6]=1[C:8]1[CH:9]=[CH:10][C:11]([C@H:14]([NH2:16])[CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(C)cc1B(O)O
Reactant: CCOc1ccc(Cl)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2c(C)nn(C)c2Cl)cc1
Agent: C[C@@H](N)c1ccc(Br)cc1
Product: COc1ccc(C)cc1-c1ccc([C@@H](C)N)cc1

Procedure:
Prepared in a similar manner to (R)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid [1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethyl]-amide (Example 1) using 2-methoxy-5-methylphenylboronic acid and (R)-1-(4-bromophenyl)ethylamine to give (R)-1-(2′-methoxy-5′-methyl-biphenyl-4-yl)-ethylamine which was then reacted with 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride. Title compound: 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, 1H), 7.27 (d, 2H), 7.20 (d, 2H), 7.12 (d, 1H), 7.02 (s, 1H), 6.97 (d, 1H), 4.35 (q, 1H), 3.72 (s, 3H), 3.55 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H), 1.33 (d, 3H) ppm; MS (ESI) m/z: value [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]1([CH2:26][CH2:27][C:28](O)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]1([CH2:26][CH2:27][C:28]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CCC1CCCCC1)C2
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Triethylamine 0.43 ml was added in a methylene chloride 20 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.49 g, and stirred at 0° C. for 40 min. 3-cyclohexyl propionic acid 0.44 ml and WSC 0.59 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 45 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ether. The ether solution was washed with 10% sodium hydroxide solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3(3-cyclohexylpropionyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 20 ml solution of lithium aluminum hydride 0.19 g and refluxed for 1.5 hour. The reaction mixture was cooled, then added ether, water and 10% sodium hydroxide solution, and filtered the insoluble material. The filtrate was extracted with ether and dried by anhydrous sodium sulfate. After removing the drying agent, the filtrate was concentrated in vacuo. The thus obtained residue was purified by means of flash column chromatography (Merck, silica gel 60 230-600 mesh, chloroform-chloroform: acetone=20:1) to obtain the product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[C:24]([Cu])#[N:25]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2cccc(Oc3ccccc3)c2c1O
Reactant: N#C[Cu]
Product: COC(=O)c1nc(C#N)c2cccc(Oc3ccccc3)c2c1O

Procedure:
The title compound was synthesized from 1-Bromo-4-hydroxy-5-phenoxy-isoquinoline-3-carboxylic acid methyl ester and CuCN in analogy to example 3a; MS-(+)-ion: M+1=320.8.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12])=[O:5])[CH3:2].N1C(C)=CC=CC=1C>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)COCCCC(=O)Cl
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)COCCCC=O

Procedure:
29 g (0.14 mol) of 4-ethoxycarbonylmethoxybutyric acid chloride are dissolved in 290 ml of tetrahydrofuran and the solution is hydrogenated under normal pressure at 10°-15° C. by addition of 5.8 g of 5% Pd/C and 18 ml of 2,6-lutidine. Upon cessation of hydrogenation, the catalyst is removed by filtration and the filtrate is concentrated by evaporation. Distillation of the crude product gives 4-ethoxycarbonylmethoxybutanal as a clear colourless liquid of b.p. 72°-74° C./2.10-2 torr.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[NH:10][N:9]=[CH:8][CH2:7]2)=[CH:2]1.[CH2:11]([N:13]=[C:14]=[S:15])[CH3:12]>C(O)C>[CH2:11]([NH:13][C:14]([N:10]1[CH:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH2:7][CH:8]=[N:9]1)=[S:15])[CH3:12]
Reactant: CCN=C=S
Reactant: C1=NNC(c2ccsc2)C1
Solvent: CCO
Product: CCNC(=S)N1N=CCC1c1ccsc1
Yield: 0.3 %

Procedure:
1.82 g (1 mol equiv.) 5-Thiophen-3-yl-4,5-dihydro-1H-pyrazole (synthesized as described in WO 2008/034863) and 1.36 mL (1.3 mol equiv.) ethyl isothiocyanate were added to 15 mL ethanol. The reaction mixture was refluxed for 5 hours, and subsequently concentrated on silica gel under reduced pressure. Purification by flash chromatography on silica gel (Et2O:PA=1:1) afforded 0.70 g (26%) 5-thiophen-3-yl-4,5-dihydro-pyrazole-1-carbothioic acid ethylamide. 1H NMR (400 MHz, CDCl3) δ 1.24 (t, J=7.2 Hz, 3H), 2.86 (ddd, J=18.5, 3.3, 1.7 Hz, 1H), 3.39 (ddd, J=18.5, 11.4, 1.7 Hz, 1H), 3.56-3.77 (m, 2H), 6.01 (dd, J=11.4, 3.3 Hz, 1H), 6.93 (dd, J=5.0, 1.0 Hz, 1H), 7.02 (t, J=1.7 Hz, 1H), 7.13 (m, 1H), 7.26 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29].[Cl-].[NH4+]>C(OCC)C.C(#N)C>[CH2:29]([O:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:20])=[C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])[CH:6]=1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: C=CCOc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Yield: 59.9 %

Procedure:
An acetonitrile (10 mL) solution of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.69 g, 2.33 mmol), potassium carbonate (0.24 g, 1.74 mmol) and allylbromide (0.22 mL, 2.56 mmol) was stirred for 4.5 hours under reflux. A saturated ammonium chloride solution (10 mL) and diethyl ether (10 mL) were added to the resulting mixture, and the organic layer was separated and then the aqueous layer was extracted with diethyl ether (10 mL×2 times). The organic layer combined was washed with a saturated sodium chloride solution (15 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/2) to obtain a white solid of 2-(5-allyloxy-4-chloro-2-fluorophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.47 g, yield:62.9%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[OH:24].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH2:2]([O:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCBr
Reactant: Cc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCCCCCCCCCCCOc1cc(C)ccc1C
Yield: 86.4 %

Procedure:
1-bromotetradecane (44.4 mL, 0.149 mol), 2,5-dimethylphenol (20.0 g, 0.164 mol) and K2CO3 (82.4 g, 0.596 mol) were combined in a round bottom flask in acetonitrile (200 mL). The flask was equipped with a stir-bar, and a water-cooled condenser and protected under a nitrogen atmosphere. The mixture was heated at reflux for overnight. Synthetic progress was monitored by the disappearance of the signal (triplet) from the C1 hydrogens on the alkyl bromide (˜3.5 ppm) in 1H NMR. Upon completion, the reaction was removed from heat and excess K2CO3 was removed by gravity filtration (rinsed with CH2Cl2). The crude product was concentrated in vacuo and the resulting material was dissolved in CH2Cl2, washed with 1 M NaOH (2×, to remove unreacted 2,5-dimethylphenol or p-cresol), dH2O (2×) and brine (1×), dried over Na2SO4, gravity filtered, and concentrated in vacuo to remove the solvent. The material was of sufficient purity (by 1H and 13C NMR) to be used in the subsequent reactions. Yielded 41.0 g (86%) of an off-white solid, mp=36.9-37.9° C. 1H NMR (CDCl3, 400 MHz) δ: 7.01 (d, 3J=7.4 Hz, 1H, Ar—H); 6.66 (d, 3J=7.6 Hz, 1H, Ar—H); 6.65 (s, 1H, Ar—H); 3.95 (t, 3J=6.5 Hz, 2H, OCH2); 2.33 (s, 3H); 2.20 (s, 3H); 1.80 (m, 2H, OCH2CH2); 1.49 (m, 2H, OCH2CH2CH2); 1.42-1.26 (m, 20H); 0.90 (t, 3J=6.8 Hz, 3H, CH2CH3). 13C NMR (CDCl3, 100 MHz) δ: 157.15, 136.40, 130.25, 123.65, 120.53, 112.01, 67.88, 31.93, 29.70, 29.68, 29,66, 29.62, 29.42, 29.40, 29.37, 26.16, 22.70, 21.40, 15.78, 14.11. HRMS (DART): [M+H]+=319.29460 (calcd for C22H39O 319.29954).
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([CH2:10][CH:11]([O:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:12]([O:14]C)=[O:13])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>O.O1CCOCC1>[C:12]([CH:11]([O:16][C:17]([N:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)=[O:18])[CH2:10][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)([OH:14])=[O:13]
Reactant: COC(=O)C(CC1CCCCC1)OC(=O)N1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C(CC1CCCCC1)OC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of phosgene (33.6 ml, 20% in toluene) was added to 3-cyclohexyl-2S-hydroxypropionic acid methyl ester (compound (11), 0.7 g, 4.03 mmol) followed by 6 drops of dimethylformamide. The mixture was stirred at ambient temperature for 16 hours then the solvents removed in vacuo. The residue was azeotroped with toluene (3×20 ml), and dissolved in anhydrous dichloromethane (11 ml). The solution was cooled to 0° C. then morpholine (0.86 g, 9.85 mmol) added. The mixture was stirred for 2 hours then partitioned between dichloromethane (30 ml) and 0.5M hydrochloric acid (30 ml). The dichloromethane layer was washed with saturated aqueous sodium hydrogen carbonate solution (30 ml), saturated aqueous sodium chloride solution (30 ml), dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by chromatography over silica gel eluting with ethyl acetate:heptane 1:1. Appropriate fractions were combined and the solvents removed in vacuo to leave morpholine-4-carboxylic acid 2S-cyclohexyl-1-methoxycarbonylethyl ester (0.13 g, 10%) as an oil. A solution of lithium hydroxide monohydrate (17.5 mg, 0.418 mmol) in water (0.76 ml) was added to an iced-water chilled solution of morpholine-4-carboxylic acid 2-cyclohexyl-1-methoxycarbonylethyl ester (110 mg, 0.367 mmol) in dioxane (1.5 ml). The mixture was stirred at ambient temperature for 1 hour then diluted with water (10 ml). The aqueous layer was extracted with diethyl ether (2×110 ml) which was discarded, then acidified to pH=2 with 6M hydrochloric acid. The product was extracted into diethyl ether (2×10 ml), then the combined ethereal layers washed with saturated aqueous sodium chloride (10 ml), dried (MgSO4) and the solvent removed in vacuo to give morpholine-4-carboxylic acid 1-carboxy-2-cyclohexylethyl ester as a white solid, yield 0.11 g, (100% from ester). TLC (single spot, Rf=0.20, methanol:dichloromethane 1:9), HPLC-MS (single main peak with Rt=7.614 mins, 286.2 [M+H]+, 287.2 [M+2H]+, 593.3 [2M+Na]+).
Reaction SMILES: C(O)C#C.[H-].[Na+].[C:7]([O-:11])(=O)[C:8]#[CH:9].[Na+].Cl[C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH3:29])[N:22]=2)[N:15]=1>O1CCCC1.C(Cl)(Cl)Cl>[CH3:20][C:18]1[CH:19]=[C:14]([O:11][CH2:7][C:8]#[CH:9])[N:15]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH3:29])[N:22]=2)[N:17]=1
Reactant: CCCc1cccc(-c2nc(C)cc(Cl)n2)n1
Reactant: C#CC(=O)[O-]
Agent: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C#CCOc1cc(C)nc(-c2cccc(CCC)n2)n1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of propargyl alcohol (0.82 g) in anhydrous tetrahydrofuran (80 ml) was added 60 % oily sodium hydride (0.58 g) to prepare sodium propargylate. To this solution was added at room temperature 4-chloro-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (3 g). The mixture was stirred for one hour and then concentrated under reduced pressure. To the redidue obtained was added chloroform (100 ml). The mixture was washed twice with water (30 ml each) and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The crystalline residue obtained was washed with hexane to obtain 4-methyl-6-propargyloxy-2-(6-n-propyl-2-pyridinyl)pyrimidine (2.7 g, yield: 83 %).
Reaction SMILES: [C:1]1([NH:7][C:8]2([CH2:14][NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]=O>ClCCl>[C:1]1([N:7]2[C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:14][N:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CNCC1(Nc2ccccc2)CCCCC1
Reactant: C=O
Solvent: ClCCl
Product: CCOC(=O)CN1CN(c2ccccc2)C2(CCCCC2)C1
Temperature: 100 °C
Yield: 98 %

Procedure:
510 mg (1.75 mmol) of ethyl [(1-phenylaminocyclohexylmethyl)amino]-acetate are dissolved in 10 ml of dichloromethane and 10 ml of formaldehyde are added. The solution is heated to 100° C. with microwaves for 30 min. The medium is poured into dichloromethane and washed with water. The organic phases are collected and then dried over sodium sulfate. The solvents are evaporated. 520 mg of ethyl (1-phenyl-1,3-diazaspiro[4.5]dec-3-yl)acetate are obtained in the form of a colorless oil. Yield=98%.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].CO[C:7]([C:9]1[CH:13]=[C:12]([C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[CH:17][CH:18]=2)[N:11]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[N:10]=1)=[O:8].[NH4+].[Cl-]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[N:11]1[C:12]([C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[CH:17][CH:18]=2)=[CH:13][C:9]([C:7]2([OH:8])[CH2:2][CH2:1]2)=[N:10]1
Reactant: COC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Reactant: CC[Mg+]
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C4(O)CC4)nn3-c3ccccc3Cl)s2)c1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A solution of EtMgBr in THF (1.0M, 11 mL) was added dropwise at it to a stirred solution of 1-(2-chloro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1H-pyrazole-3-carboxylic acid methyl ester (950 mg, 2 mmol) and Ti(OiPr)4 (0.7 mL, 2.4 mmol) in anhydrous THF (50 mL) under N2. The resulting dark mixture was stirred at it for 2 h. At 0° C. aqueous NH4Cl solution was added, extracted with Et2O. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified first by flash chromatography (0-60% EtOAc/hexanes) and then by reverse HPLC to give the title compounds as a white solid (85 mg, 0.1%). 1HNMR (CDCl3): δ 8.04 (d, 1H), 7.83-7.81 (m, 1H), 7.74-7.71 (m, 1H), 7.57-7.43 (m, 5H), 7.2 (d, 1H), 6.72 (d, 1H), 6.50 9s, 1H), 3.07 (s, 3H), 2.92 (brs, 1H), 1.31 (m, 2H), 1.17 (m, 2H). MS(ES): 471[M+H]+, 453 (M-OH).
Reaction SMILES: C(Br)C=C.[CH3:5][C:6]1[CH:11]=[C:10]2[O:12][C:7]=1[C:8]([CH3:13])=[CH:9]2>>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:13])[C:7]=1[OH:12]
Reactant: Cc1cc2cc(C)c1o2
Agent: *c1ccccc1*
Solvent: CCOCC
Solvent: C=CCBr
Product: Cc1cccc(C)c1O

Procedure:
Substantially the same reaction as in Examples 1 to 9 was conducted except that various alkenyl halides as shown in Table 5 were employed instead of allyl bromide. PPE-1 was used in Examples 17 and 18. Poly 2,6-dimethyl-1,4-phenylene ether [viscosity (ηsp/c): 0.59 (hereinafter referred to as PPE-4)] was used in Examples 19 to 21. A bifunctional polyphenylene ether obtained by oxidative polymerization of 2,6-dimethylphenol (hereinafter referred to as PPE-5) in the presence of bis (3,5-dimethyl-4-hydroxyphenyl) sulfone as a polyfunctional phenol compound was used in Example 22. Toluene/TMEDA (100 ml +2.5 ml) was used as a solvent instead of THF in Examples 19 and 22.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:52])[NH:29][C@@H:30](O[Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:31]([CH3:33])[CH3:32])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:71]1CCC[CH2:72]1>>[OH:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:52])[NH:29][C@H:30]([CH2:72][OH:71])[CH:31]([CH3:32])[CH3:33])[N:27]=2)[CH2:22]1
Reactant: C1CCOC1
Reactant: CC(C)[C@@H](NC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[(1S)-1-(t-butyldiphenylsilyloxy)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.98 g, 2.60 mmol) (obtained as described in Reference Example 36(2)) in anhydrous tetrahydrofuran (100 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (6.23 ml, 6.23 mmol) in an ice bath. The mixture was stirred in the ice bath overnight. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (95:5) as the eluant to afford 3-hydroxy-1-{4-[(1S)-1-(hydroxymethyl)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}azetidine (755 mg, yield 100%) as a colorless oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:19][O:20][C:21]1[CH:38]=[CH:37][C:36]2[C@@H:35]3[C@H:26]([C@H:27]4[C@@:31]([CH2:33][CH2:34]3)([CH3:32])[C:30](=[O:39])[C:29]([CH3:40])=[CH:28]4)[CH2:25][CH2:24][C:23]=2[CH:22]=1.C(=O)(O)[O-].[Na+]>C(OC(C)=C)(=O)C>[C:1]([O:39][C:30]1[C@:31]2([CH2:33][CH2:34][C@H:35]3[C@@H:26]([CH2:25][CH2:24][C:23]4[CH:22]=[C:21]([O:20][CH3:19])[CH:38]=[CH:37][C:36]=43)[C:27]2=[CH:28][C:29]=1[CH3:40])[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C(C)=C[C@@H]12
Agent: C=C(C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Product: COc1ccc2c(c1)CC[C@H]1C3=CC(C)=C(OC(C)=O)[C@@]3(C)CC[C@H]21
Temperature: 100 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
Acetic anhydride (80 ml) and p-toluene sulfonic acid (6 g) are added to a suspension of 3-methoxy-16-methylestra-1,3,5(10),15-tetraen-17-one (1) (DE-OS 3,023,568 (1982)) (20 g; 67.7 mmol) in isopropenyl acetate (400 ml). The reaction mixture is stirred for about 20 hours at 100° C. After cooling it is poured on ice water and neutralized by addition of small portions of sodium bicarbonate. It is extracted three times with benzene, the combined organic phases are washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The resulting brown residue (23.5 g) is chromatographed on silica gel with a mixture of ethyl acetate/benzene (1:49). The yellowish crystalline productis further purified by recrystallization of ethyl acetate/methanol. 19.8 g (87%) of colorless 14,16-diene-17-acetate (2) is obtained.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([CH2:12][CH3:13])[N:4]=1)#[N:2].[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].O>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:15][CH3:16])=[C:5]([CH2:12][CH3:13])[N:4]=1)#[N:2]
Reactant: CCc1nc(C#N)c(C#N)nc1Cl
Reactant: CCCNCCC
Solvent: O
Solvent: CC(C)=O
Product: CCCN(CCC)c1nc(C#N)c(C#N)nc1CC
Yield: 49.7 %

Procedure:
2,3-Dicyano-5-chloro-6-ethylpyrazine (1.92 g; 0.01 mole) was dissolved in 30 ml of acetone. The solution was cooled to 0° to 5° C., and with stirring, 2.02 g (0.02 mole) of di-n-propylamine was added dropwise. The mixture was stirred for 30 minutes. The precipitate was separated by filtration. The filtrate was concentrated under reduced pressure to afford a yellow oily product. Water (20 ml) was added to the oily product, and the precipitated white powder was recrystallized from ethanol to afford 1.28 g (yield 50%) of 2,3-dicyano-5-di-n-propylamino-6-ethylpyrazine.