Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][CH2:4][C:5]1([CH2:34][CH2:35][CH:36]([OH:39])CO)[CH2:10][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][C:14]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[C:33]4[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=4[CH:27]=[CH:26][CH:25]=3)=[C:15]([CH2:16][CH2:17][CH3:18])[C:7]=2[O:6]1.I([O-])(=O)(=O)=O.[Na+]>C(O)(C)(C)C.O>[O:11]=[C:9]1[C:8]2[CH:12]=[CH:13][C:14]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[C:33]4[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=4[CH:27]=[CH:26][CH:25]=3)=[C:15]([CH2:16][CH2:17][CH3:18])[C:7]=2[O:6][C:5]([CH2:4][CH2:3][CH:2]=[O:1])([CH2:34][CH2:35][CH:36]=[O:39])[CH2:10]1
Reactant: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(O)CO)(CCC(O)CO)CC2=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC=O)(CCC=O)CC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of 90 mg (0.158 mmol) of the title product of Example 66 in 3.7 ml of t-butanol was added a solution of 135 mg (0.629 mmol) of sodium periodate in 1.0 ml of H2O. After stirring at room temperature for 2 hours, the mixture was partitioned between diethyl ether and water and the aqueous layer extracted with a fresh portion of ether. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was triturated with diethyl ether to give the title compound (61 mg), m.p. 107°-108° C.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.N([O-])=O.[Na+].[I-:14].[K+].C(OCC)(=O)C>O.C1COCC1.S(=O)(=O)(O)O.[Cu]>[I:14][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1
Reactant: [I-]
Reactant: Cc1ccc(N)cc1O
Agent: [Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(I)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
10 g of 5-amino 2-methyl phenol is dissolved in a solution of 150 ml of water, 100 ml of THF and 6 ml of concentrated sulphuric acid. The resultant solution is cooled down to 0° C. A solution of 5.6 g of sodium nitrite in 30 ml of water is added dropwise at 0° C. over 40 minutes. Next the suspension obtained is agitated for 30 minutes at 0° C. and 17.5 g of potassium iodide in 70 ml of water and 200 mg of powdered metallic copper are added. The temperature is left to rise to 20° C. over 30 minutes and agitation is maintained for one hour at this temperature. The reaction medium is poured into water and extraction is carried out with ethyl acetate. The organic phases are collected, dried over magnesium sulphate and evaporated under reduced pressure. The residual oil is chromatographed, eluting with a heptane-ethyl acetate mixture (1-1), in order to give 9.7 g of 5-iodo 2-methyl phenol. M.p.=60° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[C:13]([C:23]#[N:24])=[CH:12]2)=[C:7](OC)[C:6]=1[O:27]C)[CH3:2].O1CCCC1.C(O)C.Cl>O>[CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][C:6]=1[OH:27])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3O)c2)c(OC)c1OC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3O)c2)cc1O
Temperature: 70 °C
Reaction time: 18 h
Yield: 50.7 %

Procedure:
To a solution of 4-[3-cyano-4-(2-hydroxyphenyl)pyrrole-1-yl]-2-methoxy-methoxy benzoic acid ethyl ester (0.12 g) in a mixed solvent of tetrahydrofuran (3 mL) and ethanol (5 mL) was added 2 mol/L hydrochloric acid (2 mL), and this mixture was stirred at 70° C. for 18 hours. To this reaction mixture was added water, the precipitated solid was collected by filtration, and this solid was washed with water, dried under reduced pressure at 50° C. to give the title compound (0.054 g).
Reaction SMILES: [CH:1]1([C@@H:4]2[O:14][CH2:13][C:7]3=[N:8][O:9][C@@H:10]([CH2:11][F:12])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1.C1([C@@H]2OC[C@]3([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])NOC[C@@H]3C2)CC1>>[CH:1]1([C@@H:4]2[O:14][CH2:13][C@:7]3([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])[NH:8][O:9][C@@H:10]([CH2:11][F:12])[C@@H:6]3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: Fc1ccc([C@]23CO[C@@H](C4CC4)C[C@H]2CON3)c(F)c1
Reactant: FC[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Product: FC[C@@H]1ON[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@@H]12

Procedure:
Conversion of rel-(3R,3aR,5R)-5-cyclopropyl-3-(fluoromethyl)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C43) to the product was carried out using the method described for synthesis of rel-(3aR,5R,7aS)-5-cyclopropyl-7a-(2,4-difluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C19) in Example 2. The product was obtained as an oil. Yield: 0.10 g, 0.32 mmol, 64%. 1H NMR (400 MHz, CDCl3) δ 7.93 (ddd, J=9, 9, 7 Hz, 1H), 6.90 (br ddd, J=9, 8, 2 Hz, 1H), 6.80 (ddd, J=12, 8.6, 2.5 Hz, 1H), 6.45 (s, 1H), 4.12-4.21 (m, 1H), 3.60-3.95 (m, 4H), 3.09 (br dd, J=9, 9 Hz, 1H), 2.88 (br dd, J=10, 9 Hz, 1H), 2.18 (br dd, J=14, 7.5 Hz, 1H), 1.63-1.75 (m, 1H), 0.88-0.98 (m, 1H), 0.52-0.64 (m, 2H), 0.37-0.46 (m, 1H), 0.24-0.33 (m, 1H).
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:12]1[N:16]([CH3:17])[CH:15]=[N:14][C:13]=1[CH:18]=[O:19].CS(C)=O>C(OCC)(=O)C>[C:2]1([S:8]([C:12]2[N:16]([CH3:17])[CH:15]=[N:14][C:13]=2[CH:18]=[O:19])(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccccc1
Reactant: Cn1cnc(C=O)c1Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1cnc(C=O)c1S(=O)(=O)c1ccccc1
Temperature: 180 °C
Yield: 61.2 %

Procedure:
A mixture of benzenesulfinic acid sodium salt (0.065 g), 5-bromo-1-methyl-1H-imidazole-4-carbaldehyde (0.037 g) and dimethyl sulfoxide (2.0 mL) was heated by microwave irradiation at 180° C. for 10 minutes. The mixture was treated with additional benzenesulfinic acid sodium salt (0.065 g), and heated by microwave irradiation at 180° C. for 40 minutes. The mixture was diluted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was triturated with cyclohexane to afford a yellow solid. The solid was collected by filtration, washed with cyclohexane and dried to afford the title compound (0.030 g).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[NH:4].[CH3:22][CH2:23]N(C(C)C)C(C)C.C(Cl)(=O)C>C(#N)C.C(=O)(O)[O-].[Na+]>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:11]([NH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:3]2[N:4]=[C:22]([CH3:23])[O:1][N:2]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(CC(=O)Nc2sccc2C(=N)NO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: COc1ccc(CC(=O)Nc2sccc2-c2noc(C)n2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of N-(3-(N-hydroxycarbamimidoyl)thiophen-2-yl)-2-(4-methoxyphenyl)-acetamide (104 mg, 0.341 mmol) in acetonitrile (2 mL) was added DIPEA (127 mg, 0.987 mmol) and acetyl chloride (48 μL, 0.681 mmol). The resulting solution was stirred at 60° C. for 18 h and was subsequently diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, dried (Na2SO4), filtered, concentrated under vacuum and purified by preparative HPLC to give 2-(4-methoxyphenyl)-N-(3-(5-methyl-1,2,4-oxadiazol-3-yl)thiophen-2-yl)acetamide. Retention time (min)=6.733, method [7], MS (ESI) 330.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.63 (s, 1H), 7.30-7.35 (m, 3H), 7.00 (d, J=9.2 Hz, 2H), 6.89 (d, J=6.2 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[Br:21][C:22]1[C:23]([CH3:29])=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.CO>[Br:21][C:22]1[C:23]([CH3:29])=[C:24]([NH:25][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([F:11])[CH:10]=[C:2]([F:1])[C:3]=2[N+:12]([O-:14])=[O:13])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)c1cc(F)cc(F)c1[N+](=O)[O-]
Reactant: Cc1c(N)cccc1Br
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: Cc1c(Br)cccc1NC(=O)c1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of 3,5-difluoro-2-nitrobenzoic acid (522 mg, 2.57 mmol) in DCM (10 mL) was treated with oxalyl chloride (0.337 mL, 3.86 mmol), then with DMF (3 drops). The resulting solution was stirred at room temperature for 60 min. The mixture was concentrated and the residue was re-concentrated twice from dry DCM. The residue was dissolved in DCM (10 mL) and treated dropwise with 3-bromo-2-methylaniline (478 mg, 2.57 mmol), followed by dropwise addition of TEA (0.537 mL, 3.86 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was treated with saturated aqueous NaHCO3, forming a white precipitate. The organic phase was separated, and the aqueous phase and the white solid were extracted twice with DCM, then filtered. The collected solid was washed with water and dried. The combined organic phases were dried and concentrated, and the residue was triturated with DCM to give additional solid. Both solids were combined with DCM and MeOH and concentrated to give N-(3-bromo-2-methylphenyl)-3,5-difluoro-2-nitrobenzamide (821 mg, 86% yield). Mass spectrum m/z 371, 373 (M+H)+393, 395 (M+Na)+. 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 7.98-7.90 (m, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.40 (d, J=7.7 Hz, 1H), 7.21 (t, J=7.9 Hz, 1H), 2.32 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=5[CH:32]=[O:33])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[BH4-].[Na+].Cl.C(OCC)(=O)C>CO>[F:38][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=5[CH2:32][OH:33])[O:27][N:26]=4)[N:24]=3)[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: O=Cc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4CO)C3)cs2)CC1

Procedure:
To a solution of 2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde (1.9 g) in methanol (50 ml) was added, at 0° C., sodium borohydride (0.16 g), and then the mixture was stirred at room temperature for 2 hours. Subsequently, the reaction mixture was admixed at 0° C. with 0.1 molar hydrochloric acid and ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(hydroxymethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-ethanone (1.1 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:9][CH:8]=2)[C:3]1=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: Cn1ccn(-c2ccccc2)c1=O
Product: CN1CCN(c2ccc(S(=O)(=O)Cl)cc2)C1=O
Temperature: 0 °C

Procedure:
A solution of 1-methyl-3-phenylimidazol-2-one (5.7 g, 32.3 mmol) in 10 mL of chlorosulfonic acid was stirred at ambient temperature for 30 minutes. The reaction mixture was poured into ice/water and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo to a white solid (7.4 g). Used as is in the following prep.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][CH:21]=2)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].O.[OH-].[Li+].Cl>O1CCOCC1.O>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][CH:21]=2)=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(CC)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(Cc1ccc(OCCc2ccc(CC)cc2)cc1)C(=O)O
Reaction time: 8 h
Yield: 107.8 %

Procedure:
Ethyl 2-ethoxy-3-{4-[2-(4-ethylphenyl)ethoxy]phenyl}propanoate (0.48 g, 1.3 mmol) was dissolved in dioxane (5 ml). Lithium hydroxide monohydrate (0.2 g, 4.76 mmol) in water (5 ml) was added. The mixture was stirred overnight and then acidified with 1M hydrochloric acid, pH ˜3-4. Dioxane was removed by evaporation in vacuum. The residue was diluted with water and then extracted with dichloromethane. The organic phase was washed with brine and dried with sodium sulfate. The solvent was then evaporated. 0.48 g desired product was obtained, yield 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:26][OH:27])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:28](Cl)([CH3:31])(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:26][O:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCCCNC(=O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Product: COC(=O)CCCCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(6-methoxycarbonylhexyl)propanamide (502 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(6-methoxycarbonylhexyl)propanamide (453.1 mg).
Reaction SMILES: [CH2:1](Br)[CH3:2].[Mg].C1(C)C=CC(S(O[CH2:15][C@@H:16]2[C@@H:20]([CH2:21][OH:22])[O:19][C:18]([CH3:24])([CH3:23])[O:17]2)(=O)=O)=CC=1.[Cl-].[NH4+].N>C(OCC)C.O1CCCC1.[Cu]Br.CSC>[CH3:24][C:18]1([CH3:23])[O:19][C@H:20]([CH2:21][OH:22])[C@@H:16]([CH2:15][CH2:1][CH3:2])[O:17]1
Reactant: CCBr
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2OC(C)(C)O[C@@H]2CO)cc1
Agent: [Cu]Br
Agent: N
Agent: [Cl-]
Solvent: CCOCC
Solvent: CSC
Solvent: C1CCOC1
Product: CCC[C@H]1OC(C)(C)O[C@@H]1CO
Temperature: 0 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
3.29 g (16 mmol) of copper(I) bromide/dimethyl sulfide and a Grignard reagent, prepared from 3.92 g (36 mmol) of ethyl bromide and 1.3 g (54 mmol) of magnesium in 60 ml of diethyl ether, were added in succession to a stirred solution of (4R,5R)-[5-hydroxymethyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl p-toluenesulfonate (4.62 g, 14.6 mmol) in 60 ml of tetrahydrofuran at -40° C. under argon. After stirring at 0° C. for 4 hours, the mixture was poured into a mixture of 200 ml of saturated aqueous ammonium chloride solution and 10 ml of saturated aqueous ammonia solution. The resulting 2-phase system was stirred for 20 minutes. The organic phase was then separated off and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous ammonium chloride, sodium hydrogen carbonate and concentrated sodium chloride solution. After drying over anhydrous sodium sulfate and removing the solvent, a residue remained which was chromatographed on 100 g of silica gel using ethyl acetate and n-hexane in the weight ratio 1:3 as eluent. (4R, 5R)-(2,2-Dimethyl-5-propyl-1,3-dioxolan-4-yl)methanol was obtained as a colorless oil in a yield of 83.3% ([α]D20=+27.3° (c=2.81° in trichloromethane); cf. Liebigs Ann. Chem. (1975) page 2261: [α]D25=−27.7° (c=2.8 in trichloromethane) for the enantiomer).
Reaction SMILES: [CH2:1]([CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:15]([C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][N:23]=2)=[CH:19][CH:18]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CO.C(Cl)Cl>[CH2:1]([CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:17]2[CH:32]=[CH:31][C:20]([O:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][N:23]=3)=[CH:19][CH:18]=2)[CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(CCC2CCCNC2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCC(CCc4ccccc4)C3)cc2)nc1
Yield: 49.1 %

Procedure:
Using a method similar to Example 345, using 3-phenethyl-piperidine (0.0789 g, 0.417 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.101 g, 0.417 mmol), sodium triacetoxyborohydride (0.129 g, 0.610 mmol), and acetic acid (0.038 mL, 0.664 mmol) in 1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography (25:1→8:1 methylene chloride:methanol), 0.085 g (49%) of the title compound as a white foam: high resolution mass spectrum (electrospray): m/z calc for C26H30N3O2 416.2338, found 416.2346; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.0 Hz), 8.30 (dd, 1H, J=2.4, 8.8 Hz), 7.44 (d, 2H, J=8.3 Hz), 7.30-7.24 (m, 2H), 7.20-7.13 (m, 5H), 7.05 (d, 1H, J=7.8 Hz), 3.60 (s, 2H), 3.02-2.90 (m, 2H), 2.71-2.59 (m, 2H), 2.05 (dt, 1H, J=2.0, 11.2 Hz), 1.89 (d, 1H, J=12.2 Hz), 1.82-1.69 (m, 2H), 1.68-1.52 (m, 4H), 1.00 (dq, 1H, J=3.4, 12.2 Hz).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.BrC1C=C([Cl:20])C=CC=1OC.[Li]CCCC.COB(OC)OC>>[Cl:20][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1Br
Reactant: COc1ccc(F)cc1B(O)O
Agent: COB(OC)OC
Agent: [Li]CCCC
Product: COc1ccc(Cl)cc1B(O)O
Yield: 77 %

Procedure:
This compound was prepared in a manner similar to that of 5-fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) from 2-bromo-4-chloroanisole (2.00 g, 9.0 mmol, 1.0 equivuiv), n-BuLi (2.5M in hexanes; 3.62 mL, 9.0 mmol, 1.0 equivuiv), and trimethylborate (3.0 mL, 26 mmol, 2.9 equivuiv) to afford 1.30 g (77%) of crude 5-chloro-2-methoxyphenylboronic acid as a white semi-solid. This compound was used in the next reaction with no further purification.
Reaction SMILES: [O:1]=[C:2]1[C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][NH:3]1.Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>>[Si:20]([O:19][CH2:18][CH2:17][N:3]1[CH2:4][CH2:5][CH2:6][C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:2]1=[O:1])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1=O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(CCO[Si](C)(C)C(C)(C)C)C1=O

Procedure:
(S)-tert-butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)-2-oxopiperidin-3-ylcarbamate was prepared from (S)-tert-butyl 2-oxopiperidin-3-ylcarbamate (Example 7) and (2-bromoethoxy)(tert-butyl)dimethylsilane according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 50% ethyl acetate/hexanes, to provide compound (2d) in 26% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.CCCCCC.[CH3:19][C:20](=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1)[CH3:21].Cl>O1CCCC1>[CH:22]1([C:20]([CH3:21])([CH3:19])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1
Reactant: Cc1ccccn1
Reactant: CC(C)=C1C=Cc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(Cc1ccccn1)C1C=Cc2ccccc21
Yield: 85.8 %

Procedure:
A solution of α-Picoline (1.97 ml, 20 mmol) in 10 ml of tetrahydrofuran was cooled to −20° C. and 15% n-butyl-lithium in hexane (13 ml, 20 mmol) was added during 10 min with stirring. The cooling bath was removed and the solution allowed to stir for 1 h while the temperature rose to room temperature. The resulting mixture was treated with a solution of 1-(1-methylethylidene)-1H-indene (3.12 g, 20 mmol) in 5 ml of tetrahydrofuran (5 ml) with vigorous stirring. The resulting solution was stirred for 14 h and hydrolyzed with 60 ml of 15-% hydrochloric acid. The organic layer was isolated and the aqueous phase washed once with ethyl acetate, then neutralized with aqueous ammonia solution and extracted three times with dichloromethane. The combined organic layers were dried over MgSO4, filtered and the solvent removed to give 4.28 g (86%) of 2-[2-(1H-inden-1-yl)-2-methylpropyl]pyridine as an oil. The product was NMR-pure, so no further distillation was necessary.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].Cl[C:22]([O:24][CH2:25][CH2:26]Cl)=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:26][CH2:25][O:24][C:22]1=[O:23]
Reactant: O=C(Cl)OCCCl
Reactant: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N2CCOC2=O)C1
Yield: 108.6 %

Procedure:
Analogously to example 45a), (R)-2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)phenylamine (300 mg, enantiomer B, preparation as described in WO2004085404) was reacted with 2-chloroethyl chloroformate (140 mg). 400 mg of the desired product were obtained.
Reaction SMILES: CO.C[C:4](C)([O-:6])C.[K+].F[C:10]1[CH:17]=[C:16]([C:18]2[N:22]([CH3:23])[C:21]([C:24]([CH3:36])([O:26][C:27]3[C:32]([F:33])=[CH:31][C:30]([F:34])=[CH:29][C:28]=3[F:35])[CH3:25])=[N:20][N:19]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].O>C1COCC1>[CH3:4][O:6][C:10]1[CH:17]=[C:16]([C:18]2[N:22]([CH3:23])[C:21]([C:24]([CH3:36])([O:26][C:27]3[C:32]([F:33])=[CH:31][C:30]([F:34])=[CH:29][C:28]=3[F:35])[CH3:25])=[N:20][N:19]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: CC(C)(C)[O-]
Reactant: Cn1c(-c2ccc(C#N)c(F)c2)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2nnc(C(C)(C)Oc3c(F)cc(F)cc3F)n2C)ccc1C#N
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
Methanol (0.060 ml) was added to a solution of potassium tert-butoxide (130 mg) in THF (6 ml) under ice cooling, followed by stirring for 15 minutes under ice cooling. 2-fluoro-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}benzonitrile (300 mg) was added to the reaction mixture, followed by stirring for one hour, while slowly elevating to room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 30:70 linear gradient) to obtain 2-methoxy-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}benzonitrile (192 mg), as a colorless solid.