Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC(C)CCCC(C)=CCCC(=O)C[Br:20])C1C=CC=CC=1.[O:24]([CH2:42][CH:43]([CH3:59])[CH2:44][CH2:45][CH2:46][C:47]([CH3:58])=[CH:48][CH2:49][CH2:50][C:51]([O:53][Si](C)(C)C)=[CH2:52])[Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[O:24]([CH2:42][CH:43]([CH3:59])[CH2:44][CH2:45][CH2:46][C:47]([CH3:58])=[CH:48][CH2:49][CH2:50][C:51](=[O:52])[CH2:53][Br:20])[Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=CCCC(=O)CBr)CCCC(C)COCc1ccccc1
Reactant: C=C(CCC=C(C)CCCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)O[Si](C)(C)C
Product: CC(=CCCC(=O)CBr)CCCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
Following the procedure for the preparation of 11-benzyloxy-1-bromo-6,10-dimethyl-2-oxo-undec-5-ene, but employing 11-t-butyldiphenylsiloxy-6,10-dimethyl-2-trimethylsiloxy-undec-1,5-diene (44.5 g) in place of 11-benzyloxy-6,10-dimethyl-2-trimethylsiloxy-undec-1,5-diene, 11-t-butyldiphenylsiloxy-1-bromo-6,10-dimethyl-2-oxo-undec-5-ene (45.8 g) is obtained as a yellow oil. Chromatography of a portion of the oil on silica using ethyl acetate-hexane gradients gives the pure product:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:15])([CH3:14])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:5][CH:4]=1.[CH3:16][O:17]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:15])([CH3:14])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:5][C:4]=1[CH:16]=[O:17]
Reactant: COC(Cl)Cl
Reactant: COc1ccc2c(c1)N(C)C(=O)C2(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)C(C)(C)C(=O)N2C
Reaction time: 1.5 h

Procedure:
Under nitrogen, combined 282 mg of 6-Methoxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one (1.37 mmol) with 10 ml of CH2Cl2 and chilled in ice-H2O bath. Added 4.1 ml of 1.0 M titanium tetrachloride in CH2Cl2 (4.1 mmol) dropwise. Stirred in cold for 1.5 hours. Added 186 μl of α,α-dichloromethyl methyl ether (2.06 mmol and stirred in cold for 15 minutes, then at room temperature overnight. Poured over ice-H2O, extracted three times with CH2Cl2. The combined organics were extracted with brine, sat. NaHCO3, brine, dried (MgSO4) and the solvent evaporated in vacuo to 289 mg of green solid (91%). 1H NMR (400 MHz, CDCl3) δ 1.35 (6H, s), 3.25 (3H, s), 3.98 (3H, s), 6.42 (1H, s), 7.68 (1H, s), 10.35 (1H, s), M/z (APCI+) 234.0 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]2[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=2)[CH:4]=1.[Cl-].[CH3:19][NH:20][C:21]([N:23]1[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]1)=[O:22].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH3:19][NH:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:2][C:3]2[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]3[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=3)[CH:4]=2)[CH2:25][CH2:24]1)=[O:22]
Reactant: Cc1cnc(Nc2ncc(C#N)s2)cc1CCl
Reactant: CNC(=O)N1CC[NH2+]CC1
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)N1CCN(Cc2cc(Nc3ncc(C#N)s3)ncc2C)CC1
Reaction time: 3.5 h

Procedure:
2-(4-Chloromethyl-5-methyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (9-9, 0.204 g, 0.771 mmol) and 4-methylcarbamoyl-piperazin-1-ium chloride (4-3, 0.277 g, 1.54 mmol) were dissolved in 2 mL DMSO. Diisopropylethyl amine (0.537 mL, 3.08 mmol) was added and the reaction was stirred for 3.5 hours. The reaction mixture was then directly loaded onto a reverse phase purification system to afford the titled compound, 9-10, as the TFA salt. 1H NMR (CD3OD) δ 8.35 (s, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 4.25 (s, 2H), 3.37 (bs, 4H), 3.24 (bs, 4H), 2.73 (s, 3H), 2.39 (s, 3H). MS [M+H]+=372.1. 4-(tert-Butyl-dimethyl-silanyloxymethyl)-2-chloro-3-methyl-pyridine (10-1)
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[CH:4][C:3]=1[CH2:17][NH:18][CH2:19][CH2:20][CH3:21].[N:22]#[C:23]Br>C(O)C>[NH2:22][C:23]1[N:18]([CH2:19][CH2:20][CH3:21])[CH2:17][C:3]2[C:2](=[CH:16][CH:15]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=3)[C:10]#[N:11])[CH:4]=2)[N:1]=1
Reactant: CCCNCc1cc(Oc2cccc(C#N)c2)ccc1N
Reactant: N#CBr
Solvent: CCO
Product: CCCN1Cc2cc(Oc3cccc(C#N)c3)ccc2N=C1N
Temperature: 25 °C

Procedure:
A mixture of 3-(4-amino-3-propylaminomethyl-phenoxy)-benzonitrile (0.032 mol) in ethanol (400 mL) was stirred at room temperature, and cyanogen bromide (0.038 mol) was added, and then the reaction mixture was stirred and refluxed for 2 hours. After cooling, the precipitate was filtered off, washed with diisopropyl ether and dried to yield crude product as a solid.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)=[O:12].IC.Cl>O1CCCC1>[CH3:9][O:10][C:11]([C:13]1([CH3:1])[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)=[O:12]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of lithium diisopropyl amide (1.8 M in tetrahydrofuran/heptane/ethylbenzene, 46.2 mL, 83 mmol) at −78° C. was added a solution of 4-(methoxycarbonyl)-cyclohexanecarboxylic acid (6.2 g, 33.3 mmol) in tetrahydrofuran (80 mL) over 15 minutes via cannula needle. After 40 minutes of stirring, iodomethane (3.12 mL, 49.9 mmol) was added over 30 seconds to the brown reaction mixture. After 45 minutes the reaction bath was allowed to warm to room temperature over four hours, then the reaction mixture was cooled to 0° C. before hydrochloric acid (2.0 M in water, 100 mL) was added. The reaction mixture was diluted with hexanes (50 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (3×50 mL), dried over sodium sulfate, filtered, and concentrated to give 4-(methoxycarbonyl)-4-methylcyclohexanecarboxylic acid, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:13])[C:6]=1[S:7]([CH2:10][C:11]#[N:12])(=[O:9])=[O:8].[C:14](OC)(OC)(OC)[CH3:15]>>[CH3:14][C:15]1[NH:1][C:2]2[S:3][CH:4]=[C:5]([CH3:13])[C:6]=2[S:7](=[O:9])(=[O:8])[C:10]=1[C:11]#[N:12]
Reactant: Cc1csc(N)c1S(=O)(=O)CC#N
Reactant: COC(C)(OC)OC
Product: CC1=C(C#N)S(=O)(=O)c2c(C)csc2N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (2-amino-4-methylthiophene-3-sulfonyl)acetonitrile (0.50 g) in trimethyl orthoacetate (1 ml) was heated at 120-130° C. for 2 h and then concentrated in vacuo at ˜50° C. for 1 h. The residue was suspended in a mixture of absolute ethanol (5 ml) and triethylamine (0.32 ml) and stirred at reflux for ½ h, then at 0° C. for ½ h and filtered. The filtrate was heated at reflux for one more hour, concentrated in vacuo, dissolved in ethyl acetate (10 ml) and extracted with 1 M NaOH (10 ml). The aqueous phase was washed with ethyl acetate (2×5 ml), cooled to 0° C. and acidified with 10 M HCl, pH being adjusted to 0-1. After stirring for 1 h at 0° C. the precipitate was collected by filtration and dried to give the title compound as a practically pure beige solid. Yield 0.09 g (16%). An analytically pure sample was obtained by recrystallization from methanol; mp 347-349° C. (decomp.); 1H-NMR(DMSO-d6) δ (ppm): 12.7 (br, 1H), 7.09 (s, 1H), 2.40 (s, 3H), 2.32 (s, 3H); 13C-NMR (DMSO-d6) δ (ppm): 153.9, 143.5, 131.5, 119.6, 116.6, 113.8, 89.6, 20.4, 15.3; IR 3226, 3030, 2903, 2227(C≡N), 1580, 1526, 1281 and 1134 (SO2). Elemental analysis, % found (calc. for C9H8N2O2S2): C 44.69 (44.98); H 3.22 (3.36); N 11.33 (11.66); S 26.76 (26.69).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][C@H:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O>[NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][C@H:3]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Sc2ccccc21
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
In 700 ml of dimethylformamide is dissolved 54.8 g of trans-3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. To this solution is added 8.8 g of 60% sodium hydride under ice-cooling. The reaction temperature is gradually elevated to room temperature, and the mixture is stirred for 1.5 hours. After the reaction mixture is again cooled to about 10° C., 100 ml of a dimethylformamide solution containing 25.5 ml of ethyl bromoacetate is added dropwise. After the reaction temperature is elevated again to room temperature, the mixture is stirred for 5 hours and then concentrated under reduced pressure. By adding ice-water and chloroform to the residue, the organic substance is extracted. After the chloroform layer is washed with water and dried, the solvent is distilled off under reduced pressure. By adding a mixed solution of isopropyl ether and isopropyl alcohol to the residue, the crystallization is effected. The resulting crystals are collected by filtration to give 37 g of ethyl trans-3-amino-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate.
Reaction SMILES: CO.[C:3]1([C:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH2:23](O)/[CH:24]=[CH:25]\[CH2:26][OH:27]>>[C:11]([C:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:27][CH2:26][CH:25]=[CH:24][CH2:23][O:10]1)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: OC/C=C\CO
Solvent: CO
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)C1(c2ccccc2)OCC=CCO1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
60.8 g (1.9 mols) of methanol were added with stirring to a suspension of 105 g (0.5 mol) of benzil in 107.1 g (0.9 mol) of thionyl chloride, with cooling to a temperature below 10° C. The mixture was initially stirred until room temperature was reached, and then it was stirred for 2 hours at 50° C. 52.8 g (0.6 mol) of cis-2-butene-1,4-diol were added to the clear, pale yellow solution, and volatile products were distilled off at 10 torr and 50° C. The mixture was then stirred for 3 hours at from 60° to 65° C. under normal pressure, 15 g of potassium carbonate and 200 ml of isopropanol were added, and the reaction product was precipitated by the dropwise addition of 100 ml of water. 110.4 g of 2-benzoyl-2-phenyl-4,7-dihydro-1,3-dioxepin were obtained, having a melting point of from 115° to 119° C. After recrystallizing from isopropanol, the melting point was from 118° to 119° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:27](=[O:28])[CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-phenylacetyl chloride were treated as in Example 53 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.70 (s, 1H), 8.39-8.44 (m, 1H), 7.85-8.05 (m, 2H), 7.69-7.76 (m, 1H), 7.59-7.66 (m, 4H), 7.21-7.41 (m, 5H), 3.69 (s, 2H); MS (ESI+) M/Z 390 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH2:10]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:23]([NH:22][S:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[CH2:10][CH2:11][CH2:12]3)(=[O:21])=[O:20])=[O:24])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C=NS(=O)(=O)c1ccc2c(c1)CCC2
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)NS(=O)(=O)c1ccc2c(c1)CCC2
Reaction time: 7 h
Yield: 84.7 %

Procedure:
A solution of 2.67 g of 3,4-dichloroaniline in 10 ml of toluene was added to 3.87 g of 2,3-dihydro5-indenylsulfonylisocyanate in 20 ml of toluene. After stirring 7 hours, the resulting precipitate was recovered by filtration, washed with toluene and dried providing 5.38 g of the title product, m.p. 155.5°-158° C.
Reaction SMILES: ClC1C(O[C:9](=[O:16])[C@@H:10]2[CH2:14][CH2:13][C:12](=[O:15])[NH:11]2)=C(Cl)C(Cl)=C(Cl)C=1Cl.Cl.[NH2:22][C@H:23]([C:25]([NH2:27])=[O:26])[CH3:24].C(N1CCOCC1)C>CN(C)C=O>[NH:11]1[C:12](=[O:15])[CH2:13][CH2:14][C@H:10]1[C:9]([NH:22][C@H:23]([C:25]([NH2:27])=[O:26])[CH3:24])=[O:16]
Reactant: C[C@H](N)C(N)=O
Reactant: O=C1CC[C@@H](C(=O)Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2Cl)N1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(N)=O

Procedure:
3.75 g (10 mmols) of L-pyroglutamic acid pentachlorophenyl ester were stirred in 40 ml of dimethyl formamide with 1.5 g (12 mmols) of L-alanine amide hydrochloride and 1.54 ml (12 mmols) of N-ethylmorpholine for 4 hours. The solvent was distilled off in vacuo. The residue was dissolved in methanol and the solution was stirred successively with strongly basic and strongly acid ion exchangers. The exchanger was removed by filtration and concentration to dryness followed. The residue was triturated with ethyl acetate, dissolved in a little ethanol and precipitated with petroleum ether in the form of a resin that solidified under petroleum ether. Yield: 1.2 g, chromatographically unfirom without sharp melting point.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:21]2[CH2:23][CH2:22]2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:35])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:21]2[CH2:23][CH2:22]2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:35])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 130.1 %

Procedure:
100 mg (0.29 mmol) of the compound from Example 227 were introduced into 15 ml of dichloromethane at 0° C., 72 mg (0.29 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 135 mg of the title compound as mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[C:4]([F:24])[CH:3]=1.[OH:25][C:26]([CH3:45])([CH3:44])[CH2:27][N:28]1[C:32]([CH3:33])=[C:31]([C:34](O)=[O:35])[C:30](=[O:37])[N:29]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[F:24][C:4]1[CH:3]=[C:2]([NH:1][C:34]([C:31]2[C:30](=[O:37])[N:29]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:28]([CH2:27][C:26]([OH:25])([CH3:45])[CH3:44])[C:32]=2[CH3:33])=[O:35])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][N:14]=[C:13]2[C:8]=1[C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[C:11](=[O:17])[NH:12]2
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)c(F)c1
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)c5ccccc5c34)c(F)c2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Yield: 33.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 209 using Compound 182 (55 mg, 0.17 mmol) and 1-(2-hydroxy-2-methyl-propyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (60 mg, 0.21 mmol) to provide 210 (34 mg, 33% yield) as a white solid. LC-MS (M+H=594, obsd.=594).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1>CN(C)C=O.C(OCC)C>[F:14][C:13]([F:16])([F:15])[C:10]([CH2:12][N:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1)([OH:11])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: C1CSCCN1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CCSCC1)C(F)(F)F

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (see Example 1) (130 mg) and thiomorpholine (84.6 μL) in dimethylformamide (1 μL) was heated at 100° C. for 15 hours. The resulting mixture was diluted with diethyl ether, washed with water and brine, dried over sodium sulfate, filtered, and the volatiles removed in vacuo. The residue was purified by silica gel column chromatography using 2% EtOAc-hexanes as the eluent. The product-rich fractions were concentrated in vacuo to provide the title compound as a clear oil (161 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:40])OC3C=CC=CC=3)[CH2:26]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1)(=[O:3])[NH2:2].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.CCN(CC)CC>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:40])[CH2:26]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1)(=[O:3])[NH2:2]
Reactant: C1COCCN1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)Oc3ccccc3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)N3CCOCC3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Yield: 45.7 %

Procedure:
A solution of (R)-phenyl 1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyridin-2-yl)piperidin-3-ylcarbamate (30 mg, 0.055 mmol), morpholine (7.20 mg, 0.083 mmol), and Et3N (0.012 mL, 0.083 mmol) in CH2Cl2 (2 mL) was heated at 50° C. overnight. The reaction mixture was diluted with CH2Cl2, washed with satd. NaHCO3 and water, and concentrated. The residue was purified by prep-HPLC and the product containing fractions were collected, neutralized with saturated NaHCO3, extracted with CH2Cl2, separated, and concentrated to obtain 13.5 mg of (R)—N-(1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino) pyridin-2-yl)piperidin-3-yl)morpholine-4-carboxamide as a light yellow solid as free base.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Mg]Br.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18](=[O:21])[CH2:19][CH3:20])[CH:15]=[CH:16][CH:17]=1.[Cl-].[NH4+].Cl>C1COCC1.O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])([OH:21])[CH2:19][CH3:20])[CH:15]=[CH:16][CH:17]=1
Reactant: CCC(=O)c1cccc(OC)c1
Reactant: Cc1ccccc1[Mg]Br
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)(c1cccc(OC)c1)c1ccccc1C
Reaction time: 8 h
Yield: 438.6 %

Procedure:
To a solution of 2-methylphenyl magnesium bromide (prepared from 4.9 g magnesium turnings and 24 ml of 2-bromotoluene) in dry THF (300 ml) was added dropwise a solution of 3'-methoxypropiophenone (25.9 g, 0.16 mol) in dry THF (200 ml). When addition was complete the mixture was heated at reflux temperature for 2 h. Water (250 ml) was added followed by a saturated ammonium chloride solution (250 ml) and the mixture was left overnight. A 4 N hydrochloric acid solution was added until a clear solution was obtained and the phases was separated. The organic phase was dried over magnesium sulphate and the solvent evaporated in vacuo. The residue was submitted to flash chromatography on silica gel (690 g) using a gradient of n-heptane in ethyl acetate to give 28.2 g (55%) of 1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propanol. A mixture of 1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propanol (26.2 g, 0.10 mol), isopropanol (300 ml) and a 6 N solution of sulphuric acid (150 ml) was stirred at room temperature for 2 h. The reaction mixture was neutralised with a 4 N sodium hydroxide solution and extracted with ethyl acetate (2×200 ml). The combined organic phases was dried over magnesium sulphate and the solvent was evaporated in vacuo. The residue was submitted to flash chromatography on silica gel (800 g) using n-heptane as eluent to give 18.4 g (76%) of 1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([CH2:10][CH3:11])=[CH:5][O:6][CH2:7][CH2:8][Cl:9].[H][H]>C(O)C.[Ni]>[CH3:1][O:2][C:3](=[O:12])[CH:4]([CH2:10][CH3:11])[CH2:5][O:6][CH2:7][CH2:8][Cl:9]
Reactant: [H][H]
Reactant: CCC(=COCCCl)C(=O)OC
Agent: [Ni]
Solvent: CCO
Product: CCC(COCCCl)C(=O)OC
Yield: 82 %

Procedure:
37 g of 3-(2-Chloroethoxy)-2-ethylacrylic acid methyl ester (0.192 mole) was dispersed in 350 ml ethanol together with 6 g Raney nickel catalyst. The mixture was hydrogenated in a pressure vessel at 55°-60° C. at a hydrogen gage pressure of 30-60 atmospheres. When no further hydrogen was absorbed, the contents of the vessel were filtered to remove the catalyst, the solvent was distilled off, and the residue was fractionated in a vacuum. 3-(2-Chloroethoxy)-2-ethylpropionic acid methyl ester was obtained in an amount of 30.7 g (33.7 g) as a fraction boiling at 110° C. and 14 torr (82%-90% yield). nD20 =1.4399, d420 =1.083.
Reaction SMILES: [H][H].[F:3][C:4]([F:15])([F:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1>C(O)(C)C.[Rh]>[F:3][C:4]([F:14])([F:15])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1
Reactant: Oc1ccc(CCC(F)(F)F)cc1
Reactant: [H][H]
Agent: [Rh]
Solvent: CC(C)O
Product: OC1CCC(CCC(F)(F)F)CC1

Procedure:
At 50° C. and 150 bar hydrogen pressure, 40.7 g of 4-(3,3,3-trifluoropropyl)phenol in 800 ml of isopropanol were hydrogenated using rhodium on carbon as catalyst for 20 h. The catalyst was filtered off and the reaction solution was concentrated, to give the title product as a colourless solid which was reacted further without any purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:25][S:26]([C:29]1[CH:38]=[CH:37][C:32](/[CH:33]=[CH:34]/[CH:35]=O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][C@@H:19]1[CH2:20][O:21][C@@H:35](/[CH:34]=[CH:33]/[C:32]2[CH:37]=[CH:38][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=2)[O:23][CH2:22]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CS(=O)(=O)c1ccc(/C=C/C=O)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/c2ccc(S(C)(=O)=O)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 58 %

Procedure:
Reaction and treatment were carried out in the same manner as in Example 4 using (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol and trans-4-(methylsulfonyl)cinnamaldehyde to obtain the title compound, a major product as an oil in a yield of 58%.