Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]([F:22])([F:21])[CH2:12]OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:12][C:11]([F:22])([F:21])[F:10]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Cl)cc1Br
Temperature: 100 °C
Yield: 108 %

Procedure:
A mixture of 2-bromo-4-chloro-phenol (2.0 g, 9.6 mmol), trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (3.8 g, 16.4 mmol), potassium carbonate (8.0 g, 59 mmol), and N,N-dimethylformaldehyde (80 ml) was heated to 100° C. for 72 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was treated with water (150 ml) and extracted with ethyl acetate (160 ml). The organic extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:4) to give 2-bromo-4-chloro-1-(2,2,2-trifluoro-ethoxy)-benzene (3.0 g, 100% yield). 1H NMR (acetone-d6) δ 4.80 (q, 2H, J=8.4 Hz, CH2), 7.28 (d, 1H, J=8.9 Hz, Ar), 7.45 (dd, 1H, J=8.9 Hz, J=2.5 Hz, Ar), 7.69 (d, 1H, J—2.5 Hz, Ar).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:30]([O:29][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][C:6]([OH:37])=[O:5])[CH:14]=[CH:13][C:12]=1[N:15]1[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[S:16]1(=[O:28])=[O:27])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCC(=O)O)cc2OCc2ccccc2)S1(=O)=O

Procedure:
A solution of 3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid tert-butyl ester (420 mg, 0.77 mmol) in 6 mL of TFA/methylene chloride (1:1) is stirred at RT for 20 min. The solvent is removed under reduced pressure. Methylene chloride is added and removed (4×) to give the title compound as an oil: (M−1)−=489.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH:25][CH2:26][C@@H:27]3[C@H:32]([CH3:33])[CH2:31][CH2:30][CH2:29][NH:28]3)=[N:22][C:21]=2[CH:34]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH:25][CH2:26][C@@H:27]3[C@H:32]([CH3:33])[CH2:31][CH2:30][CH2:29][N:28]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[S:15][CH:14]=[N:13][CH:12]=3)=[O:9])=[N:22][C:21]=2[CH:34]=1
Reactant: Cc1ccc(-c2cncs2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-c2cncs2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(thiazol-5-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 481 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH2:8]2.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:14]([NH:21][CH:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:8]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc2c1CCC(=O)C2
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc2c1CCC(NCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
To a solution of 5-methoxy-2-tetralone (30 g, 170.24 mmol) dissolved in CH2Cl2 (250 mL) were added benzylamine (23 mL, 212.80 mmol) and AcOH (0.97 mL, 17.02 mmol), and the mixture was stirred for 4 h at room temperature. It was then cooled to 0° C. and NaB(OAc)3H (0.38 eq, 13.71 g, 64.69 mmol) was added over a period of 20 min. After 1 h stirring at 0° C., NaB(OAc)3H (1.07 eq, 38.61 g, 182.16 mmol) was added over a period of 30 min. It was added CH2Cl2 (100 mL), the reaction mixture warmed to room temperature and stirred for 15 h. The mixture was cooled again to 0° C., and H2O (200 mL) was added slowly. The pH of the solution was adjusted to 8.0 by adding NaHCO3 saturated aqueous solution (300 mL), and the mixture was stirred at 0° C. for 15 min. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (2×150 mL). All organic phases were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue (58.7 g) was purified by flash chromatography on silica gel (40:60:1-100:0:1 AcOEt/Hexane/Et3N), followed by trituration with hexane, affording 33.87 g of the title compound (Rf=0.5 (10% MeOH/CH2Cl2), yellow solid, 74% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11][C@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:13]([OH:19])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:3]=1.N1C(C)=CC=CC=1C.O([Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])S(C(F)(F)F)(=O)=O.CCN(C(C)C)C(C)C.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.C1COCC1>C(Cl)Cl>[Si:44]([O:19][C@H:13]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)[C@@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH2:11][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(Cl)c2c(c1)OCO2)[C@H](O)c1nccs1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(Cl)c2c(c1)OCO2)[C@H](O[Si](C)(C)C(C)(C)C)c1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A suspension of tert-butyl (1S,2S)-3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-hydroxy-1-(thiazol-2-yl)propan-2-ylcarbamate (3.250 g, 8 mmol) in DCM (24 mL) was treated with 2,6-lutidine (1 ml, 12 mmol) followed by tert-butyldimethylsilyl triflate (2 ml, 9 mmol) and was allowed to stir at RT for 2 hours. An additional equivalent of TBS triflate was added followed by an additional equivalent of base. After 1 hour, DIEA (2 ml, 12 mmol) was added, followed by di-tert-butyldicarbonate 1M in THF (8 ml, 8 mmol), and the reaction mixture was allowed to stir at RT overnight. The reaction mixture was quenched with 2N HCl solution, diluted with DCM, and washed with saturated NaHCO3 solution and brine. The organics were dried over MgSO4 and concentrated under reduced pressure. Purification of the crude residue by column chromatography gave tert-butyl (1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-(thiazol-2-yl)propan-2-ylcarbamate (1.850 g, 45% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][NH:11][CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>C1COCC1.C(Cl)Cl>[CH3:10][N:11]([CH2:5][C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=1)[CH3:12]
Reactant: CNC
Reactant: O=Cc1cccc(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(O)c1

Procedure:
3-Hydroxybenzaldehyde (1.0 g), 2M dimethylamine in THF (5 mL), and sodium triacetoxyborohydride (2 g) in CH2Cl2 (10 mL) were stirred for 24 hours. The mixture was treated with methanol and chromatographed on silica gel with 2-25% ethyl acetate/hexanes.
Reaction SMILES: [Mg].[CH2:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]Br)[CH3:3].[F:11][C:12]([F:19])([F:18])[C:13](OCC)=[O:14].[Cl-].[NH4+]>C(OCC)C>[CH2:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:13](=[O:14])[C:12]([F:19])([F:18])[F:11])[CH3:3]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCOCCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOCCCCCC(=O)C(F)(F)F
Temperature: -20 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
A Grignard reagent which was prepared from 6.4 g (0.27 mol) of magnesium turnings and 48.7 g (0.25 mol) of 5-bromopentyl ethyl ether was added over 45 minutes to a solution of 35.5 g (0.25 mol) of ethyl trifluoroacetate in 300 ml of diethyl ether at -60° C. After stirring for further 2 hours, the temperature was increased to -20° C. and a saturated aqueous ammonium chloride solution was added. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was distilled under the reduced pressure, to obtain 31 g of 7-ethoxy-1,1,1-trifluoro-2-heptanone. Boiling point; 90-92° C. (47 mmHg).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1)[C:3]([O:5][CH3:6])=[O:4].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:13][C:9]1[N:8]=[C:7]([CH:2]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:3]([O:5][CH3:6])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: C1COCCN1
Reactant: COC(=O)C(Br)c1cccc(Br)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(c1cccc(Br)n1)N1CCOCC1

Procedure:
Methyl bromo(6-bromopyridin-2-yl)acetate (1.00 g, 3.24 mmol) was taken up in DMF (10 mL) and morpholine (367 μL, 4.21 mmol) and DIEA (848 μL, 4.86 mmol) were added. After maintaining the reaction at room temperature overnight, the reaction was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. Silica gel chromatography (0-100% EtOAc/hexanes) afforded the title compound as a yellow oil.
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[H][H]>CC(O)C>[OH:1][C@@H:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CCCCCC(=O)c1ccccc1
Reactant: [H][H]
Solvent: CC(C)O
Product: COC(=O)CCCCC[C@@H](O)c1ccccc1
Reaction time: 12 h
Yield: 98 %

Procedure:
Chiral hydrogenation of methyl 7-oxo-7-phenylheptanoate was carried out (see formula (11) below). That is, a reaction was carried out in accordance with the procedures of Example 4 using the (S, SS)-ruthenium hydride complex (1.5 mg; 0.00125 mmol) synthesized in Example 2 and using methyl 7-oxo-7-phenylheptanoate (587 mg; 2.5 mmol) as the substrate and 2-propanol (2.5 mL) as the solvent. However, the hydrogen pressure was set to 8 atmosphere, the reaction temperature was set to 25° C., and the reaction time was set to 12 hours. As a result, methyl (R)-7-hydroxy-7-phenylheptanoate was obtained at a conversion rate of 100%, isolation yield of 98% (588 mg; 2.48 mmol), and enantiomeric excess of 95%. The enantiomeric excess was determined by HPLC analysis of the corresponding benzoic acid ester. HPLC (column: CHIRALPAC AD: size: 4.6 mm×250 mm; made by Daicel Chemical Industries Ltd.; solvent: hexane/2-propanol=19:1; temperature: 30° C.; UV wavelength: 254 nm; flow rate: 0.5 ml/minute; tR of methyl (R)-7-benzoyloxy-7-phenylheptanoate: 20.8 minutes (97.6%); tR of the Sisomer:25.9 minutes(2.4%)); [α]28D+29.1° (c:1.09;CHCl3); absolute structure: R. The absolute structure was determined from the value of the angle of rotation of 1-phenylheptanol obtained by conversion.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:12])[CH:7]=[CH:8]N(C)C)=[CH:2]1.O1C[CH2:16][CH2:15][CH2:14]1.C([Li])(C)C>CCCCC>[CH3:14][CH:15]([CH2:8][CH2:7][C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:12])[CH3:16]
Reactant: CN(C)C=CC(=O)c1ccoc1
Reactant: C1CCOC1
Agent: [Li]C(C)C
Solvent: CCCCC
Product: CC(C)CCC(=O)c1ccoc1
Temperature: -30 °C

Procedure:
A mixture of 1.65 g. (0.01 moles) of 1-(3-furanyl)-3-(dimethylamino)-2-propen-1-one and 100 ml. of anhydrous tetrahydrofuran was prepared and cooled to -30° C. and there was added thereto 5.5 ml. of a 1.85 M solution of isopropyllithium in pentane. The reaction mixture was stirred for about one-half hour at -30° C. The reaction product mixture was worked up by adding 5 ml. of water and concentrating the resulting mixture in vacuo. The residue which remained was taken up in methylene dichloride, the solution washed successively with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate concentrated in vacuo. The material which remained was chromatographed on silica gel using methylene dichloride and then 95% methylene dichloride-5% ethyl acetate as eluent. The first product off the column was the desired material, the yield of which was 600 mg. and was identified by NMR spectrum as 1-(3-furanyl)-4-methyl-2 -penten-1-one. The structure of this product was further established by hydrogenation of the 1-(3-furanyl)-4-methyl-2-penten-1-one in ethanol and over 5% palladium on carbon to yield perillaketone, a naturally-occurring furanoterpene originally isolated from Perilla frutescens Brit. by Goto, J. Pharm. Soc. Japan, 57, 77 (1937).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:11][C:10](=O)[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:14]1([CH2:13][N:9]2[CH2:10][CH2:11][CH:7]([CH2:5][NH:4][CH2:3][CH2:2][OH:1])[CH2:8]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(NCCO)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCNCC1CCN(Cc2ccccc2)C1
Yield: 77.5 %

Procedure:
A mixture of 46.66 g (0.178 mole) of N-(2-hydroxyethyl)-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide in 200 ml of tetrahydrofuran was added dropwise to a slurry of 20.25 g (0.534 mole) of lithium aluminum hydride in 150 ml tetrahydrofuran. The reaction was refluxed three hours, then cooled in an ice bath. The work up consisted of sequential addition of 20 ml water, 20 ml 15% sodium hydroxide then 60 ml water. The reaction was filtered and the precipitate washed with ethanol. The filtrate was concentrated at reduced pressure, the residue taken up in dichloromethane, dried over magnesium sulfate, and the solvent removed at reduced pressure to give 32.31 g of 2-[[[1-(phenylmethyl)-3-pyrrolidinyl]methyl]amino]ethanol as an oil. This material was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:19]=[CH2:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28](O)=[O:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:21])=[O:29]
Reactant: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethenylbenzonitrile (630 mg, 2.081 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (576 mg, 2.081 mmol) and HOBT (414 mg, 2.71 mmol) in DMF (10.0 ml) was added EDC (479 mg, 2.497 mmol) and the reaction mixture was stirred at rt for 30 minutes. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (1125 mg, 2.004 mmol, 96% yield), 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (t, 1H), 7.92 (s, 1H), 7.77 (s, 1H), 7.43-7.49 (m, 1H), 7.32-7.42 (m, 2H), 7.22 (s, 1H), 6.72 (dd, 1H), 6.02 (d, 1H), 5.48 (s, 2H), 5.41 (d, 1H), 4.47 (d, 2H), 3.37 (t, 2H), 0.74 (t, 2H), −0.10 (s, 9H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([Cl:19])=[C:15]([CH3:18])[CH:16]=3)[O:11][C:10](=[O:20])[C:9]=2[CH2:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[C:32]([F:35])([F:34])[F:33])=[O:23])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.[C:41]([O:45][CH2:46][CH2:47][CH2:48][CH3:49])(=[O:44])[CH:42]=[CH2:43].C([O-])(=O)C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O.C(OCC)(=O)C>[Cl:19][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([C:4]3[CH:3]=[C:2](/[CH:43]=[CH:42]/[C:41]([O:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:44])[CH:7]=[CH:6][CH:5]=3)=[C:9]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[C:32]([F:35])([F:33])[F:34])=[O:23])[C:10](=[O:20])[O:11]2)=[CH:16][C:15]=1[CH3:18]
Reactant: Cc1cc2c(-c3cccc(Br)c3)c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(=O)oc2cc1Cl
Reactant: C=CC(=O)OCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)/C=C/c1cccc(-c2c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(=O)oc3cc(Cl)c(C)cc23)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
A mixture of 2-[4-(3-bromophenyl)-7-chloro-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide (2.00 g), palladium acetate (0.0079 g) and tri-o-tolyl phosphine (0.0214 g) was placed in a reaction vessel, and nitrogen was passed through the reaction vessel for 10 minutes to replace the atmosphere of the reaction vessel with nitrogen. N,N-Dimethylformamide (10 ml), butyl acrylate (0.677 g) and sodium acetate (0.317 g) were added successively thereto, and the mixture was stirred at room temperature for about 20 minutes. Then, the mixture was stirred at 110° C. for 3 hours and cooled to room temperature. Ethyl acetate (20 ml) and water (20 ml) were poured to the reaction mixture and, after stirring, an organic layer was separated. The organic layer was washed successively with a mixture of 10% saline (18 ml) and conc. hydrochloric acid (2 ml), and 10% saline (20 ml). Activated charcoal (0.1 g) and tributyl phosphine (0.0712 g) were added to the organic layer, and the mixture was stirred at room temperature for 10 minutes. Then, the activated charcoal was removed by filtration and washed with ethyl acetate (4 ml). The combined filtrate and washings were concentrated to 6.0 g under reduced pressure, and n-heptane (12 ml) was added dropwise to the residue to precipitate crystals. After stirring at 5° C. for 1 hour, the crystals were collected by filtration and washed with cold ethyl acetate/n-heptane (1/3, 4 ml). A mixture of the resulting crystals (2.06 g) and acetone (10 ml) were heated to 50° C. to dissolve the mixture, activated charcoal (0.1 g) was added thereto, and the mixture was stirred for 10 minutes. The activated charcoal was removed by filtration, and washed with acetone (4 ml). Water (4.6 ml) was added dropwise to the combined filtrate and washings, and the mixture was stirred at 5° C. for 1 hour. Crystals were collected by filtration, and washed with cold acetone/water (2/1, 4 ml) to obtain the title compound (1.84 g, yield 84.9%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[B:20](OC)([O:23]C)[O:21]C.Cl>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][C:12]([B:20]([OH:23])[OH:21])=[N:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COB(OC)OC
Reactant: c1ccc(COCn2cccn2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccn(COCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-benzyloxymethyl-1H-pyrazole (200 mg, 1.06 mmol) in THF (5 mL) at 0° C. is added n-BuLi (0.51 mL of 2.5M in THF, 1.28 mmol) and the mixture is stirred at 0° C. for 30 min. To this is added trimethyl borate (551 mg, 5.3 mmol) dropwise then the mixture is allowed to warm to RT overnight. The light yellow solution is acidified with 1N HCl (12.8 mL) and the THF is removed under reduced pressure. The aqueous phase is purified by reverse phase MPLC using a gradient of 0-60% MeCN/water as eluent. The solvent is concentrated until a precipitate forms. The mixture is cooled to 0° C. and the solid filtered to give the title compound.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:34][C:35]1[CH:36]=[C:37]([OH:42])[CH:38]=[CH:39][C:40]=1[Cl:41].[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][C:53]2([CH2:60][CH2:59][CH:58](O)[CH2:57][CH2:56]2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>C(OCC)C>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][C:53]2([CH2:60][CH2:59][CH:58]([O:42][C:37]3[CH:38]=[CH:39][C:40]([Cl:41])=[C:35]([Cl:34])[CH:36]=3)[CH2:57][CH2:56]2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
Diisopropylazo dicarboxylate (315 mg, 1.56 mmol) in diethyl ether (2 mL) was added slowly to an ice cooled solution of triphenylphosphine (582 mg, 2.22 mmol) in diethyl ether (5 mL). The reaction mixture was stirred for 20 min. 3,4-Dichlorophenol (290 mg, 1.78 mmol) in diethyl ether (2 mL) was added and stirred 30 min at 0° C. and 9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (400 mg, 1.48 mmol) in diethylether (5 mL) was added and the mixture stirred at room temperature over night. Evaporation followed by flash chromatography (heptane/ethylacetate 9:1) gave 340 mg (56%) of 9-(3,4-dichloro-phenoxy)-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]([S:23][CH2:24][C@@H:25]([CH3:29])[C:26](Cl)=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([S:23][CH2:24][C@H:25]([CH3:29])[C:26]([N:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH2:11][C:12]([OH:14])=[O:13])=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)CNC1Cc2ccccc2C1
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)Cl
Product: C[C@@H](CSC(=O)c1ccccc1)C(=O)N(CC(=O)O)C1Cc2ccccc2C1

Procedure:
By reacting N-(2-indanyl)glycine with 3-benzoylthio-2(R)-methylpropionyl chloride in a similar manner to that of Example 37, there is obtained N-(3-benzoylthio-2(R)-methylpropionyl)-N-(2-indanyl)glycine as colorless needles.
Reaction SMILES: [N:1]#[C:2][NH2:3].[CH:4]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[C:9]([CH:20]([CH3:22])[CH3:21])[C:8]=1[N:23]=[C:24]=[N:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:6])[CH3:5]>ClCCCl>[C:2]([NH:3][C:24]([NH:23][C:8]1[C:9]([CH:20]([CH3:22])[CH3:21])=[CH:10][C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:7]=1[CH:4]([CH3:6])[CH3:5])=[N:25][C:26]([CH3:29])([CH3:27])[CH3:28])#[N:1]
Reactant: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1N=C=NC(C)(C)C
Reactant: N#CN
Solvent: ClCCCl
Product: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1NC(=NC(C)(C)C)NC#N

Procedure:
0.46 g of cyanamide are added to a solution of 3.5 g of N-(2,6-diisopropyl-4-phenoxyphenyl)-N'-tert-butylcarbodiimide [prepared in accordance with Example 1 (compound 4) of European patent application A-175 649] in 20 ml of 1,2-dichloroethane. The reaction mixture is refluxed for 21 hours and then concentrated by evaporation to a suspension. This concentrated suspension is stirred with diethyl ether and the crystalline product so obtained is filtered with suction. Melting point 206°-207° C. (recrystallisation from diethyl ether/hexane).