Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[Mg].Br[C:14]1[CH:23]=[CH:22][C:17]2[O:18]CCO[C:16]=2[CH:15]=1>C1COCC1>[O:11]1[C:4]2[CH:9]=[CH:8][C:7]([C:17]3([OH:18])[CH2:22][CH2:23][CH2:14][CH2:15][CH2:16]3)=[CH:6][C:5]=2[O:3][CH2:2][CH2:1]1
Reactant: Brc1ccc2c(c1)OCCO2
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc3c(c2)OCCO3)CCCCC1
Reaction time: 16 h

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (7.8 g, 50 mmole) in 50 ml dry THF was added to a of the Grignard reagent prepared from magnesium metal (1.34 g, 55 mmole) and 6-bromo-1,4-benzodioxane (10.75 g, 50 mmole). The mixture was stirred for 16 hr, quenched with saturated NH4Cl and extracted with ether. The ether extracts were dried with Na2SO4 and the solvent removed in vacuo. Acetone (75 ml) and 1 N HCl (75 ml) were added and the solution was stirred 18 hr to give a tan precipitate which was filtered and air dried (6.38 g, 59.1%). This material was used without further purtification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: OC1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCC(O)CC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and piperidin-4-ol according to conditions described in general procedure C. Mp: 182-184° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.15 (bs, 2 H), 1.58 (s, 8 H), 3.00 (bs, 2 H), 3.27 (s, 4 H), 3.61 (m, 1 H), 3.95 (bs, 2 H), 4.64 (d, J=4.0 Hz, 1 H), 6.19 (d, J=5.5 Hz, 1 H), 6.96 (d, J=12.8 Hz, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.40 (d, J=8.4 Hz, 1 H), 7.46 (s, 1 H), 7.55-7.59 (m, 3 H), 7.82 (d, J=8.0 Hz, 1 H), 7.97 (d, J=8.4 Hz, 1 H), 8.22-8.24 (m, 1 H), 10.43 (s, 1 H).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH2:10][Cl:11])([CH3:9])[CH3:8])=[CH:3][CH:2]=1.[CH:18]([Li])(CC)C.CN(C)CCN(C)C.CI.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH3:8])([CH3:9])[CH:10]([Cl:11])[CH3:18])=[CH:3][CH:2]=1
Reactant: [Li]C(C)CC
Reactant: C[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(Cl)[Si](C)(C)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
A solution of 4.0 g (15.3 mmol) of (1,1'-biphenyl-4-yl)chloromethyldimethylsilane in 20 ml of tetrahydrofuran was cooled to -78°, and 12.5 ml (16.8 mmol) of 1.35 molar sec-butyllithium in hexane was slowly dripped in followed by addition of 2.42 ml (16.1 mmol) of tetramethylethylenediamine. After stirring for one hour at -78°, the solution was warmed to -55° and 1.43 ml (22.9 mmol) of methyl iodide in 5 ml of tetrahydrofuran was added dropwise. The mixture was stirred another 30 minutes at -50°, warmed to room temperature, poured into saturated aqueous ammonium chloride, and extracted with ether. The ether extracts were washed with water and brine, dried over magnesium sulfate, and evaporated to give 3.33 g (65%) of the title compound contaminated by about 18% of an impurity: nmr (CDCl3) 0.3 (s, 2.7H, impurity), 0.4 (6H, s), 1.5 (3H, d, J=7 Hz), 3.5 (1H, q, J=7 Hz) and 7.3-7.7 (m, 13H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:19])OC1C=CC=CC=1.[F:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[C:25]([F:27])[CH:26]=1>>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][C:11]([N:31]1[CH2:30][CH2:29][N:28]([C:23]2[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=2)[CH2:33][CH2:32]1)=[O:19]
Reactant: Cc1cc(O)c(NC(=O)Oc2ccccc2)cc1C
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Product: Cc1cc(O)c(NC(=O)N2CCN(c3cc(F)cc(F)c3)CC2)cc1C
Yield: 80 %

Procedure:
Phenyl N-[2-hydroxy-4,5-dimethylphenyl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 228 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccn3)c3cc(Cl)ccc23)c1
Temperature: 0 °C

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.050 g, 0.15 mmol) and 2-(bromomethyl)pyridine hydrobromide (0.049 g, 0.175 mmol) were dissolved in DMF:THF (1:1, 4 mL) and the mixture was cooled to 0° C. Cesium carbonate (0.122 g, 0.373 mmol) was added and the reaction was warmed to 90° C. for 30 minutes. The reaction as submitted to aqueous workup and silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[S:9][CH2:10][CH2:11][C:12]2=[O:14]
Reactant: COc1ccccc1SCCC(=O)O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc2c1SCCC2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a solution of 3-[(2-methoxyphenyl)thio]propanoic acid (5.0 g, 23.6 mmol) in dry DCM (50 mL) at 0° C. is added oxalyl chloride (6.01 g, 4.09 mL, 47.2 mmol, 2 Eq) followed by few drops of DMF. The reaction mixture is stirred at 0° C. for 30 minutes. After 30 minutes, the solvent is removed under reduced pressure. To a solution of the acid chloride in DCM (150 mL) at 0° C. is added a solution of tin (IV) chloride in DCM (26 mL, 1 M, 26.0 mmol, 1.1 Eq) and the reaction mixture is stirred for 2 h. The reaction is quenched by addition of water and the product is extracted with DCM. The organic layer is dried over MgSO4, concentrated under reduced pressure. The crude residue is purified by flash chromatography (eluent: ethyl acetate/hexane 4/6) to afford 3.2 g of the title compound as a white solid.1H NMR (DMSO-d6, 400 MHz): δ 7.59-7.57 (m, 1H), 7.18 (m, 2H), 3.84 (s, 3H), 3.24-3.21 (m, 2H), 2.84-2.81 (m, 2H). MS (ESI+): 196.0. HPLC (max plot) 89.4%; Rt 3.36 min.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:6][CH2:5]2.C1(PCCCPC2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.O.[C:50]([O:53][CH2:54]C)(=[O:52])C>CN(C)C=O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([O:18][C:17]([N:16]([CH3:24])[CH2:15][CH2:14][CH2:13][N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:50]([O:53][CH3:54])=[O:52])[CH:3]=2)[C:8]1=[O:12])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(C)=O
Reactant: CN(CCCN1CCc2cc(O)ccc2C1=O)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(PCCCPc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CCN(CCCN(C)C(=O)OC(C)(C)C)C2=O
Temperature: 65 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
The resulting tert-butyl [3-(6-hydroxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propyl]methylcarbamate was dissolved in a mixed solvent (11 mL) of N,N-dimethylformamide and methanol (10:1), palladium acetate (65 mg, 0.291 mmol), 1,3-diphenylphosphinopropane (120 mg, 0.291 mmol) and triethylamine (0.405 mL, 2.91 mmol) were added, and the mixture was stirred at 65° C. under a carbon monoxide atmosphere for 16 hours. After the reaction was completed, water was added to the reaction mixture, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 1:1, v/v) to give the title compound (535 mg; yield, 100%) as a colorless oily substance.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:13][C:14]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][O:15]1)(C(C)(C)C)(C)C>CO>[CH2:27]([O:26][C:25]1[CH:24]=[CH:23][C:12]([CH2:13][C:14]2([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][O:15]2)=[CH:11][C:10]=1[CH2:9][OH:8])[CH3:28]
Reactant: CCOc1ccc(CC2(C(=O)OC)CCCO2)cc1CO[Si](C)(C)C(C)(C)C
Solvent: CO
Product: CCOc1ccc(CC2(C(=O)OC)CCCO2)cc1CO
Yield: 108.6 %

Procedure:
A solution of 0.409 g of methyl 2-[3-(t-butyldimethylsilanyloxymethyl)-4-ethoxybenzyl]tetrahydro-2-furancarboxylate in 20 ml of methanol was treated with 0.400 g of Dowex 50X ion-exchange resin for 6 hours, then the reaction mixture was filtrated and evaporated. The residue was purified by silica gel column chromatography, to give 0.320 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20](O)[CH3:21]>>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([C:15]([O:17][CH2:20][CH3:21])=[O:16])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Temperature: 0 °C

Procedure:
A suspension of 5-(benzyloxy)-1,4-dihydro-4-oxo-2-pyridinecarboxylic acid (8.24 g, 33.6 mmole) in 120 ml of ethanol was cooled to 0° C. and treated with a stream of dry HCl for 15 minutes. The resulting mixture was heated at 50° C. for 5.5 hours. The volatiles were removed in vacuo and the residue was treated with water. While cooling, the pH was raised to 7 with saturated potassium bicarbonate and the resulting mixture was extracted with dichloromethane. The extracts were washed with brine and dried over sodium sulfate. Filtration and concentration in vacuo produced 7.32 g of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([C:8]1[CH:17]=[C:16]2[C:12](=[CH:13][CH:14]=[C:15]2[CH3:18])[C:11]([CH:19]([CH3:23])[CH2:20][CH2:21][OH:22])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].N1C=CC=CC=1>ClCCl>[C:1]([O:22][CH2:21][CH2:20][CH:19]([C:11]1[C:12]2[C:16](=[CH:17][C:8]([CH:5]([CH3:7])[CH3:6])=[CH:9][CH:10]=1)[C:15]([CH3:18])=[CH:14][CH:13]=2)[CH3:23])(=[O:3])[CH3:2]
Reactant: Cc1ccc2c(C(C)CCO)ccc(C(C)C)cc1-2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCC(C)c1ccc(C(C)C)cc2c(C)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.8 g (0.063 mol) of acetyl chloride in 20 ml of dichloromethane were added dropwise at 0° C. to a solution of 12.1 g (0.05 mol) of 3-(7-isopropyl-1-methylazulen-4-yl)butanol and 7.9 g (0.1 mol) of pyridine in 100 ml of dichloromethane, and the mixture was stirred at room temperature for 1 hour. It was then extracted with 30 ml of 2N hydrochloric acid, and the organic phase was washed neutral and dried over sodium sulfate. The residue remaining behind after evaporating off the solvent was chromatographed (silica gel; 9:1 v/v petroleum ether/ethyl acetate). This gave 12.6 g (89%) of the acetate as a highly viscous blue oil. Physical data: IR (KBr): 2959, 2929 (CH); 1741 (C=O); 1555, 1463, 1436, 1387, 1365, 1241, 1047 cm-1. 1H-NMR (CDCl2): δ=1.38 (d, 6H); 2.05 (s, 3H); 2.16 (cm, 2H); 2.68 (s, 3H); 3.08 (cm, 1H); 2.22 (cm, 2H); 4.18 (cm, 2H); 6.95 (d, 1H); 7.30 (d, 1H); 7.40 (d, 1H); 7.64 (d, 1H); 8.18 (s, 1H) ppm. 13C-NMR (CDCl3); δ=1286; 20.85; 24.72 (2C); 30.17; 34.53; 38.28; 64.22; 112.19; 124.41; 125.46; 133.30; 135.13; 136.39; 136.59; 137.28; 140.04; 147.55; 170.90 ppm. MS: m/e=284.4 (C19H24O2+, 50%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.[O:19]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:42])[NH:26][C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)=[N:20]1.CN(C=O)C.Cl>C(O)C.O.COCCOC>[OH:11][C:8]([C:6]1[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=[C:2]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:25]([NH:24][C:21]3[CH:22]=[CH:23][O:19][N:20]=3)=[O:42])=[CH:32][CH:31]=2)[N:7]=1)([CH3:10])[CH3:9]
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3ccon3)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)O)nc(Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: C[C@H]1COCCN1c1cc(C(C)(C)O)nc(-c2ccc(NC(=O)Nc3ccon3)cc2)n1
Temperature: 100 °C
Yield: 20.1 %

Procedure:
2-[2-Chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]propan-2-ol (160 mg, 0.59 mmol) was added to 3-(1,2-oxazol-3-yl)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (242 mg) and Dichlorobis(triphenylphosphine) palladium catalyst (21 mg) in an 18% DMF in a mixture of 7:3:2 DME:water:ethanol (6 mL). The reaction was heated to 100° C. for 30 minutes in the microwave reactor and cooled to RT. The reaction mixture was acidified with 2M hydrochloric acid and the crude material loaded onto a SCX (10 g) column, the desired material was eluted with 7N ammonia in methanol. The material was further purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material (52 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:50]=[CH:49][C:11]([C:12]([O:32][CH2:33][C@H:34]2[O:38][C@@H:37]([N:39]3[CH:47]=[C:45]([CH3:46])[C:43](=[O:44])[NH:42][C:40]3=[O:41])[CH2:36][C@@H:35]2[OH:48])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH2:25])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6].C(N(C(C)C)CC)(C)C.C(CC[O:64][P:65](Cl)[N:66](C(C)C)C(C)C)#N>ClCCl>[P:65]([O:48][C@@H:35]1[C@@H:34]([CH2:33][O:32][C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:11]2[CH:49]=[CH:50][C:8]([O:7][CH2:1][CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6])=[CH:9][CH:10]=2)[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH2:25])=[CH:17][CH:18]=2)[O:38][C@@H:37]([N:39]2[CH:47]=[C:45]([CH3:46])[C:43](=[O:44])[NH:42][C:40]2=[O:41])[CH2:36]1)([NH2:66])[OH:64]
Reactant: C=CC=CCCOc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OCCC=CC=C)cc2)cc1
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC=CCCOc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2OP(N)O)(c2ccccc2)c2ccc(OCCC=CC=C)cc2)cc1
Temperature: 0 °C
Yield: 85.4 %

Procedure:
Compound 31 (3.0 grams, 4.43 mmol) was dissolved in anhydrous dichloromethane and diisopropylethylamine (2.7 mL; 15.5 mmol) was added. The solution was cooled to 0° C. and 2-cyanoethyl-N,N-diisopropylchlorophosphoramidite (2.0 mL, 8.86 mmol) was added. The reaction mixture was allowed to warm to room temperature with stirring under argon. After 4 hours the solution was diluted with dichloromethane and washed with a 5% aqueous solution of sodium bicarbonate (2×). The organic phase was dried (MgSO4), concentrated in vacuo, and purified by column chromatography (silica gel; EtOAc/hexane, 3/7) to afford 2.8 grams (72%) of compound 32 as a fluffy white solid. 1H NMR (300 MHz, CDCl3) δ 1.01-1.20 (m, 12H), 1.41 (s, 3H), 2.25-2.67 (m, 8H), 3.26-4.22 (m, 11H), 4.60-4.65 (m, 1H), 5.02 (dd, J=1.5, 10.4 Hz, 2H), 5.14 (dd, J=1.5, 17.3 Hz, 2H), 5.69-5.84 (m, 2H), 6.11-6.48 (m, 5H), 6.82 (dd, J=3.2, 8.9 Hz, 4H), 7.16-7.43 (m, 9H), 7.62 (d, J=15.2 Hz, 1H), 8.05 (bs, 1H); 31P NMR (300 MHz, DMSO-d6) 152.9, 152.4; Anal. Calcd for C50H61N4O8P1 (877.0276): C, 68.48; H, 7.01; N, 6.39. Found: C, 68.48; H, 7.22; N, 6.33. ##STR18##
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:20][C:21](=[O:40])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33](Br)[CH:32]=2)=[CH:26][C:25]=1[CH3:39]>>[CH3:39][C:25]1[CH:26]=[C:27]([O:30][C:31]2[CH:32]=[C:33]([O:18][C:9]3[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:34]=[C:35]([CH3:37])[CH:36]=2)[CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][C:21]([OH:40])=[O:20]
Reactant: Oc1cc(C(F)(F)F)ccc1Oc1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2cc(C)cc(Br)c2)cc1C
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2cc(C(F)(F)F)ccc2Oc2ccccc2)c1
Yield: 34 %

Procedure:
The compound of 2-phenoxy-5-trifluoromethyl-phenol is reacted with 3-[4-(3-bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester as in Example 18 to afford 0.262 g (34%) of the title compound. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C30H25O5F3 522, found 523 (M+1, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH2:8])[C:6]#[N:7])[CH3:2].N1C=CC=CC=1.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>ClCCl>[CH2:1]([O:3][C:4](=[O:9])[CH:5]([C:6]#[N:7])[NH:8][C:19](=[O:20])[CH2:18][O:17][CH3:16])[CH3:2]
Reactant: COCC(=O)Cl
Reactant: CCOC(=O)C(N)C#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C#N)NC(=O)COC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 66.6 %

Procedure:
A solution of aminocyanacetic acid ethyl ester (1.00 g, 7.80 mmol) in dichloromethane (15.00 ml) was cooled to 0° C. and treated with pyridine (0.62 g, 7.80 mmol). Methoxy-acetyl chloride (0.85 g, 7.80 mmol) was added dropwise during 15 min. The mixture was stirred for 5 min at 0° C., then warmed to room temperature and stirred for 10 min. The volatiles were evaporated, and the residue was redissolved in dichloromethane and washed twice with water. The organic layer was dried with sodium sulphate and evaporated. The residue was triturated in diisopropyl ether to yield cyano-(2-methoxy-acetylamino)-acetic acid ethyl ester (1.04 g, 66%), MS (ISP): m/e=201.1 (M+H+).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:20]=[CH:19][C:10]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=1.[CH3:21][O:22][C:23]([C:25]1[CH2:26][N:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:28][CH2:29][C:30]=1OS(C(F)(F)F)(=O)=O)=[O:24].[NH4+].[Cl-]>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH3:21][O:22][C:23]([C:25]1[CH2:26][N:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:28][CH2:29][C:30]=1[C:7]1[CH:20]=[CH:19][C:10]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=1)=[O:24]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
BuLi (1.6M in hexanes, 27.0 mL, 43.1 mmol) was added to a sol. of (4-bromophenoxy)-tert-butyldimethylsilane (12.4 g, 43.1 mmol) in THF (300 mL) at −78° C. The mixture was stirred for 30 min at −78° C., and ZnCl2 (1M in THF, 52.4 mL, 52.4 mmol) was added. The mixture was allowed to warm to rt, and a sol. of 4-trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (WO 2004/002957; 12.0 g, 30.8 mmol) in THF (20 mL) and Pd(PPh3)4 (1.00 g, 0.863 mmol) were added. The mixture was stirred at rt overnight, and aq. sat. NH4Cl was added. The mixture was extracted with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:9→1:1) yielded the title compound (13.3 g, 96%). LC-MS: tR=1.20 min; ES+: 448.35.
Reaction SMILES: [CH2:1]([C:7]1[N:8]=[C:9]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[S:10][C:11]=1[CH:12]=[CH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]([O:26][CH3:27])=[O:25])=[C:18]([CH3:28])[CH:17]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>CO.O1CCCC1.[C].[Pd]>[CH2:1]([C:7]1[N:8]=[C:9]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[S:10][C:11]=1[CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:18]([CH3:28])[CH:17]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [H][H]
Reactant: CCCCCCc1nc(-c2ccc(C)cc2)sc1C=CC(=O)c1ccc(C=CC(=O)OC)c(C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCc1nc(-c2ccc(C)cc2)sc1CCC(=O)c1ccc(CCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
The obtained methyl 3-[4-[3-[4-hexyl-2-(4-methylphenyl)thiazol-5-yl]propenoyl]-2-methylphenyl]acrylate (112 mg, 0.230 mmol) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL). 10% palladium carbon (22 mg) was added to the solution to cause replacement of hydrogen in the system. The mixture was stirred at room temperature for 3 hours. The reaction mixture was filtrated with Celite. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with hexane/ethyl acetate (5:1, v/v) to give the desired compound (46 mg) as colorless oil (yield 41%).