Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[N:29][N:28]=[N:27]4)=[CH:22][CH:21]=3)[N:17]=2)[CH2:9]1)=O)(C)(C)C.[ClH:31]>ClCCl.CO.O1CCOCC1>[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH:30]=[N:29][N:28]=[N:27]4)=[CH:24][CH:25]=3)[N:17]=2)[CH2:9]1.[ClH:31]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: c1cc(-n2cnnn2)ccc1OCc1csc(C2CCNC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (from Example 102) (411 mg, 0.959 mmol) in dichloromethane (10 mL) and methanol (2 mL) were treated with 1 mL of 4N HCl in dioxane. The resulting solution was stirred at room temperature for 30 minutes. The solvents were removed in vacuo to afford the desired product as an HCl salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](O)=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:15][CH:12]1[CH2:14][CH2:13]1
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: NC1CC1
Product: Clc1ccccc1CCNC1CC1

Procedure:
Synthesized according to typical procedures C and D from (2-chlorophenyl)-acetic acid and cyclopropylamine.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[F-:14].[Cs+].O.Cl>CS(C)=O>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([F:14])[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: [F-]
Agent: Cl
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=S1(=O)N=C(F)Nc2cc(Cl)sc21
Temperature: 155 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
A mixture of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (257 mg, 1.0 mmol) and cesium fluoride (456 mg, 3.0 mmol) in dry DMSO (1 ml) was stirred for 16 h at 155° C. in a sealed flask. Water (3 ml) was added to the cooled mixture followed by 4M hydrochloric acid to pH <2. The precipitated beige solid was isolated by filtration, washed with water and dried to give 193 mg (80%) of the title compound; 1H-NMR (DMSO-d6): δ7.09 (s, 1H), 7.34 (br s, 1H; MS: m/e 240/242 (M+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[C:11]([O:15][C:16]([CH2:18][S:19][C:20]([CH3:32])([CH3:31])[C@H:21]([NH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:22](O)=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:22](=[O:23])[C@@H:21]([NH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:20]([S:19][CH2:18][C:16]([O:15][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:17])([CH3:31])[CH3:32])=[O:10]
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)(C)SCC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Product: CCOC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC)C(C)(C)SCC(=O)OC(C)(C)C
Yield: 52.4 %

Procedure:
Reaction of 0.44 g of (L)-proline methyl ester hydrochloride and 0.86 g of 3-tert.-butoxycarbonylmethylsulfanyl-2-(R)-ethoxycarbonylamino-3-methyl-butyric acid according to the procedure described in example 91b yielded 0.60 g (52%) of the title compound as a colorless oil (+)-APCI-MS: 474 (MH+).
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[CH2:17][CH2:16][CH:15]2[CH:13]([CH2:14]2)[C:12]1([C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[OH:18])[CH3:9]>CC(=O)CC>[ClH:6].[CH3:9][N:8]([CH2:10][CH:11]1[CH2:17][CH2:16][CH:15]2[CH:13]([CH2:14]2)[C:12]1([C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[OH:18])[CH3:7]
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CC1CCC2CC2C1(O)c1cc(O)cc(F)c1
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add H2O (18 mg, 1.0 mmol) and TMSCl (92 mg, 0.857 mmol) to a solution of 3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol (218 mg, 0.781 mmol) in 2-butanone (70 mL). Then stir the reaction mixture at room temperature for 2 hours. After removal the solvent by evaporation, wash the residue with EtOAc (3 mL×2) to give 3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol hydrochloride as white solid (72 mg, Yield: 67.8%). 1H NMR (400 MHz, D2O) δ 6.93 (s, 1H), 6.87-6.89 (d, J=9.6, 1H), 6.42-6.58 (m, 1H), 3.32-3.33 (t, J=3.2, 1H), 2.98-3.04 (m, 1H), 2.77 (m, 6H), 2.22-2.23 (m, 1H), 2.06 (m, 1H), 1.81-1.85 (m, 2H), 1.61-1.71 (m, 1H), 1.17-1.21 (m, 1H), 1.08-1.10 (m, 1H), 0.83-0.86 (m, 1H), 0.56-0.60 (m, 1H).
Reaction SMILES: C([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][CH2:13][CH:12]2[OH:22])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.C(OC(=O)C)C.[Pd]>[C:16]1([N:15]2[C:11]3([CH2:23][CH2:24][NH:8][CH2:9][CH2:10]3)[CH:12]([OH:22])[CH2:13][CH2:14]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OC1CCN(c2ccccc2)C12CCN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: OC1CCN(c2ccccc2)C12CCNCC2

Procedure:
(RS)-8-Benzyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (7.8 mmol) was dissolved in methanol (100 ml) and ethylacetate (100 ml). Palladium on carbon (10%, 0.2 g) was added and the mixture was hydrogenated at room temperature and normal pressure. Filtration and evaporation yielded the desired product. 1.8 g (99%) (RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol as a beige solid, m.p. 141-144° C. and MS: m/e=232 (M+).
Reaction SMILES: [CH:1]1([C:6]2[CH2:10][CH2:9][C:8](=[O:11])[C:7]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+]>C1C=CC=CC=1.C(O)(=O)C>[CH:1]1([C:6]2[CH2:10][CH2:9][C:8](=[O:11])[C:7]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1cccc(C2=C(C3CCCC3)CCC2=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: O=C1CCC(C2CCCC2)=C1c1cccc(CO)c1

Procedure:
A mixture of 120 mg 3-cyclopentyl-2-iodo-2-cyclopenten-1-one, 80 mg 3-formylphenylboronic acid and 20 mg tetrakis(triphenylphosphine)palladium was stirred at 80° C. overnight in 8 ml toluene, 4 ml ethanol and 4 ml 2 N aqueous sodium carbonate. Then the reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/ethyl acetate=2:1) to yield 70 mg of 3-cyclopentyl-2-(3-formylphenyl)-2-cyclopenten-1-one. 3-cyclopentyl-2-(3-formylphenyl)-2-cyclopenten-1-one in benzene was stirred with one drop of acetic acid and 100 mg sodium triacetoxyborohydride at 70-80° C. for 2 hours. Then the reaction mixture was poured into saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/ethyl acetate=2:1) to yield 40 mg of 3-cyclopentyl-2-(3-hydroxymethylphenyl)-2-cyclopenten-1-one, which was then condensed with hydroxylamine hydrochloride according to a procedure similar to that described in STEP 4 for Example 1 to afford 20 mg of 3-cyclopentyl-2-(3-hydroxymethylphenyl)-2-cyclopenten-1-one oxime as a solid. 1H NMR (CDCl3, 300 MHz): δ 8.75 (bs, 1H), 7.40-7.29 (m, 3H), 7.12 (d, J=7.2 Hz, 1H), 4.66 (s, 2H), 2.98 (m, 1H), 2.75 (m, 2H), 2.61 (m, 2H), 1.71 (m, 4H), 1.55 (m, 4H).
Reaction SMILES: [C:1]([C:3]([C:16](=[O:32])[N:17]([CH2:28][CH:29]1CC1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=[CH:4][NH:5][C:6](=[NH:15])[N:7]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]1=[O:14])#[N:2].C(O)(=O)[C:34](O)=[O:35]>C(O)(=O)C>[CH3:34][O:35][CH2:29][CH2:28][N:17]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=1)[C:16]([C:3]1[C:1]([NH2:2])=[N:15][C:6]([N:7]2[CH2:11][C:10]([CH3:12])([CH3:13])[NH:9][C:8]2=[O:14])=[N:5][CH:4]=1)=[O:32]
Reactant: O=C(O)C(=O)O
Reactant: CC1(C)CN(C(=N)NC=C(C#N)C(=O)N(CC2CC2)c2cccc(C(F)(F)F)c2)C(=O)N1
Solvent: CC(=O)O
Product: COCCN(C(=O)c1cnc(N2CC(C)(C)NC2=O)nc1N)c1cccc(C(F)(F)F)c1
Yield: 146.5 %

Procedure:
As in Example 118 and starting from 4.52 g (10 mmol) of a compound II (R1, R2 =CH3 ; R3, R5, R6 =H; R4 =CH3OCH2CH2), 360 mg of anhydrous oxalic acid and 7 ml of glacial acetic acid, 2.65 g (=58.6% yield) of pure 4-amino-2-(4,4-dimethyl-2-oxo-1-imidazolidinyl)-pyrimidine-5-carboxylic acid N-(2-methoxyethyl)-N-(3-trifluoromethylphenyl)amide were obtained, melting point 192°-93°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:35][CH2:34]3)=[C:26]([C:28]([O:30]C)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].Cl.CCOCC>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:32][N:33]3[CH2:34][CH2:35][N:36]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH2:37][CH2:38]3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CN1CCN(c2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CN3CCN(c4ccccc4)CC3)s1)CC2
Reaction time: 8 h

Procedure:
Compound 62A (50 mg, 0.066 mmol) in DCM (3.5 ml) was treated with 2 N hydrogen chloride in ether (3.31 ml, 6.62 mmol) for 30 min. The reaction was concentrated and the residue was dissolved in THF (3 ml) and methanol (3 ml). NaOH (10% aq., 1 ml) was added. The resulting mixture was stirred overnight and concentrated. The residue was purified by purified by reverse phase HPLC (mobile phase: 0%-70% acetonitrile in 0.1% TFA aqueous solution during 40 min) to provide the title compound: 1H NMR (400 MHz, DMSO-D6) δ ppm 12.91 (1H, s), 8.02 (1H, d), 7.78 (1H, d), 7.70 (1H, d), 7.44-7.50 (2H, m), 7.41 (1H, t), 7.35 (1H, t), 7.20-7.27 (2H, m), 6.96 (2H, d), 6.84 (1H, t), 4.89 (2H, s), 4.73 (2H, s), 3.82 (2H, t), 3.45 (8H, s), 3.07 (2H, t). LCMS (APCI) m/e 611 (M+H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:16]([C:17]([NH2:19])=[O:18])[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:8](=[O:9])[CH2:7][C:5]=2[CH:6]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>ClCCl>[CH:1]1[CH:2]=[CH:3][C:4]2[N:16]([C:17]([NH2:19])=[O:18])[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C@@H:8]([OH:9])[CH2:7][C:5]=2[CH:6]=1
Reactant: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)N1c2ccccc2C[C@H](O)c2ccccc21
Reaction time: 2 h
Yield: 91 %

Procedure:
A solution of phenyl boronic acid (19.4 gm), D-(−)-tartaric acid (23.8 gm), calcium hydride (13.3 gm) in acetonitrile (300 mL) was heated to about 80-85° C. for about 1 hr. The reaction mass was cooled to 25-30° C. (‘Solution X’). A solution of oxcarbazepine (20 gm) in acetonitrile (100 mL) was prepared separately. ‘Solution X’ obtained above was added to the solution of oxcarbazepine followed by stirring the reaction mass for about 2 hrs. To the resulting solution sodium borohydride (4.5 gm) was added at about 30-35° C. The reaction mass was stirred at the same temperature for about 8 hrs. The pH of the resulting solution was adjusted to 1-2 by adding HCl (3N, 200 mL) followed by stirring for about 30 minutes. To the resulting solution, NaOH (20% w/v) solution was added to adjust the pH at about 12-13. Dichloromethane was added to the resulting solution followed by stirring. The organic layer was separated and distilled to obtain the title compound (Yield: 91%; HPLC purity: 98.6%; Chiral purity: 92.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][CH:4]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:22].N1CCCCC1.Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][C:14]2=[O:22])=[CH:5][CH:4]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)CC2
Temperature: 130 °C
Yield: 33.9 %

Procedure:
A mixture of 0.5 g 6-methoxy-1-indanone, 1.23 g oxindole and 2.7 ml piperidine in 4 ml of dimethylforamide was heated in a sealed tube 130° C. for 3 days to yield a greenish-black suspension. The mixture was added to 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The resulting solid was precipitated from methylene chloride/hexanes (3×) to afford 290 mg 3-(6-methoxyindan-1-ylidene)-1,3-dihydroindol-2-one as a yellowish-brown solid.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:30][O:31][C:32](=[O:38])[C@@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1.CCN(C(C)C)C(C)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:30][O:31][C:32](=[O:38])[C@@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@@H]1CCCN1C(=O)c1ccccc1C(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
6.20 g (27.5 mmol) of o-benzoylbenzoic acid was dissolved in 150 ml of methylene chloride at 25° C. under a nitrogen atmosphere. The solution was cooled to 10° C. and 4.08 g (30.2 mmol) of 1-hydroxybenzotriazole hydrate was added, followed by 5.0 g (30.2 mmol) of L-proline methyl ester HCl and followed by 6.22 g (30.2 mmol) of N,N'-diisopropylethylamine. Lastly, 6.22 g (30.2 mmol) N,N'-dicyclohexylcarbodiimide (DCC) was added which produced a slight exothermic reaction and the mixture was then stirred for 12 hours, after which time tlc analysis indicated complete consumption of starting material. A standard work-up was performed which involved removing precipitated urea by filtration and washing the filtrate with 5% sodium bicarbonate solution, 1N sodium hydroxide solution, 1N hydrochloric acid and brine. The organic phase was dried over magnesium sulfate and evaporated in vacuo to afford a yellow residue. Purification by flash chromatography on silica gel (40:1/methylene chloride:methanol) gave a yield of 6.4 g (69%) of the title compound as a cloudy gum which crystallized on standing. TLC (90:10/CH2Cl2 :MeOH): Rf =0.80. mp=128-130. 1H NMR (CDCl3) δ: 7.40-7.85(m,9H); 4.25-4.55(m,1H); 3.40-3.75(m,5H); 1.85-2.40(m,4H). I.R. (KBr): 1622, 1661, 1739, 1745 cm-1. Standard Combustion Analysis: C,71.20; H,5.68; N,4.15. Found: C,70.63; H,5.53; N=4.36. High Resolution Mass Spectrum: m/e=338.1384±0.8 ppm (calculated for C20H20NO).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29]O>>[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29][N:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:16][CH:15]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1Nc2ccc(F)cc2C1=CO
Reactant: Nc1ccc(OCCCN2CCCCC2)cc1
Product: O=C1Nc2ccc(F)cc2C1=CN(c1ccccc1)c1ccc(OCCCN2CCCCC2)cc1
Yield: 66.1 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-piperidin-1-yl-propoxy)-phenylamine (0.57 g, 1.3 equiv.) and 5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (0.363 g, 2 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (379 mg, 47%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]([CH2:26][CH2:27]O)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[O:11])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[C:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][CH:13]([N:12]2[CH2:27][CH2:26][C@H:9]([O:8][C:5]3[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=3)[C:10]2=[O:11])[CH2:18][CH2:17]1)=[O:20])([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@H](CCO)Oc2ccc(Br)nc2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(Br)nc3)C2=O)CC1
Temperature: 0 °C
Yield: 74.7 %

Procedure:
A solution of (S)-tert-butyl 4-(2-(6-bromopyridin-3-yloxy)-4-hydroxybutanamido)piperidine-1-carboxylate (1.30 g, 2.84 mmol) and tributylphosphine (689 mg, 3.40 mmol) in toluene (15 mL) was degassed with nitrogen bubble for 10 minutes and then cooled to 0° C. Di-tert-butyl diazene-1,2-dicarboxylate (784 mg, 3.4 mmol) dissolved in toluene (5 mL) and was added over a 5 minute period. The reaction was allowed to warm to ambient temperature over 12 hours. The reaction was concentrated in vacuo and purified by silica gel chromatography eluting with 1:1 hexanes/EtOAc to yield (S)-tert-butyl-4-(3-(6-bromopyridin-3-yloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (934 mg, 75%) as an off-white solid.
Reaction SMILES: CCN(CC)CC.C(O)=O.[O:11]=[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:17]=1)[CH2:13][C:14]#[N:15]>CCOC(C)=O.O>[OH:11][C@@H:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:17]=1)[CH2:13][C:14]#[N:15]
Reactant: N#CCC(=O)c1cccc(OCC2CCOCC2)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: N#CC[C@@H](O)c1cccc(OCC2CCOCC2)c1
Reaction time: 0.33 h

Procedure:
The solution of Et3N (0.78 g, 7.6 mmol) in EtOAc (50 mL) was cooled to 0° C. for 15 min. HCOOH (0.88 g, 19 mmol) was added dropwise to the reaction mixture and the solution was stirred for 20 min at same temperature. The solution of 0.2 mol % (R,R)RuCl-TsDPEN(p-cymene) (10 mg) in EtOAc was added to the reaction mixture, followed by addition of ketonitrile (13) (1.0 g, 3.8 mmol) in EtOAc at 0° C. The reaction mixture was stirred for 18 h at rt. After completion of the reaction (as monitored by TLC) the reaction mixture was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (100-200 silica mesh, 20-25% EtOAc in hexanes) gave (R)-3-hydroxy-3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propanenitrile (14) as a white solid. Yield (0.75 g, 75%); 1H NMR (400 MHz, DMSO-d6) δ 7.24 (t, J=8.0 Hz, 1H), 6.98-6.95 (m, 2H), 6.83 (dd, J=8.0, 4.0 Hz, 1H), 5.92 (d, J=4.8 Hz, 1H), 4.85 (dd, J=11.2, 4.8 Hz, 1H), 3.89-3.81 (m, 4H), 3.35-3.30 (m, 2H), 2.84 (dq, J=16.8, 4.8 Hz, 2H), 2.04-1.96 (m, 1H), 1.69-1.66 (m, 2H), 1.37-1.27 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>[Cr]([O-])([O-])=O.[Cu+2]>[CH3:1][C:2](=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)O
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Product: CCCCCCC(C)=O

Procedure:
The preparation of ketones by the dehydrogenation of secondary alcohols in the liquid phase using a copper chromite catalyst is described by D. D. Nanvati, J. Ind. Chem. Soc 51 (5), 551-2 (1974). The products are recovered by filtration and subsequent purification by distillation. An almost quantitative yield of 2-octanone was obtained from 2-octanol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[O:13][C:14](=[O:30])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:19][CH2:18]3)[N:16]=2)[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[NH:31]C(=O)OCC1C=CC=CC=1.Br.C(OCC)C>C(O)(=O)C>[NH2:31][C:3]1[C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[C:10]([C:12]2[O:13][C:14](=[O:30])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]([F:28])([F:27])[F:29])[CH2:19][CH2:18]3)[N:16]=2)=[CH:11][C:2]=1[Cl:1]
Reactant: O=C(Nc1c(Cl)cc(-c2nn(C3CCN(CCCC(F)(F)F)CC3)c(=O)o2)c2c1OCCO2)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1c(Cl)cc(-c2nn(C3CCN(CCCC(F)(F)F)CC3)c(=O)o2)c2c1OCCO2
Temperature: 25 °C
Reaction time: 7 h
Yield: 89.3 %

Procedure:
1.72 g (2.88 mmol) of phenylmethyl [6-chloro-8-[5-oxo-4-[1-(4,4,4-trifluorobutyl)piperidin-4-yl]-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,4-benzodioxin-5-yl]carbamate and 17 ml of acetic acid are introduced into a 100 ml round-bottomed flask, 5 ml of 33% hydrobromic acid in acetic acid are added and the mixture is stirred at room temperature for 7 h. Diethyl ether is added to the precipitate which has formed and 1.8 g of hydrobromide are collected by filtration. It is taken up in water and chloroform, sodium hydroxide is added in order to release the base and, after the usual treatment of the organic phase, 1.19 g of compound are obtained. Melting point: 188° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH3:34].[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38].CCOCC.Cl>N1C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:37](=[O:38])[N:36]([CH3:40])[CH3:35])=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([OH:33])([C:25]([F:26])([F:27])[F:28])[C:29]([F:32])([F:31])[F:30])=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH3:34]
Reactant: Cc1oc(-c2ccc(O)cc2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1oc(-c2ccc(OC(=O)N(C)C)cc2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A solution of 25 mg (0.052 mmol) 4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-oxazol-2-yl}-phenol (example 99) in 1 mL of pyridine was treated with 28 mg (0.26 mmol) of dimethyl carbamoylchloride and stirred at 60° C. for 2 hours. Et2O and aqueous HCl were added and the phases separated. The aqueous phase was extracted with Et2O and the combined organic phases dried over Na2SO4. Evaporation of the solvent and column chromatography on silica gel with n-heptane/EtOAc 1:1 yielded 19 mg (66%) of dimethyl-carbamic acid 4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-oxazol-2-yl}-phenyl ester, light yellow solid, MS: 556 (MH+).