Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH2:2]([O:4][C:5](=[O:28])/[C:6](/[O:25][CH2:26][CH3:27])=[CH:7]/[C:8]1[C:16]2[O:15][CH:14]=[CH:13][C:12]=2[C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:9]=1)C.[H][H].Cl>CO.C1COCC1>[CH3:2][O:4][C:5](=[O:28])[CH:6]([O:25][CH2:26][CH3:27])[CH2:7][C:8]1[C:16]2[O:15][CH:14]=[CH:13][C:12]=2[C:11]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)c2ccoc12)OCC
Reactant: [H][H]
Agent: Cl
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCc2ccccc2)c2ccoc12)C(=O)OC
Temperature: 0 °C
Reaction time: 12 h
Yield: 99.1 %

Procedure:
Magnesium turnings (0.5 g, 20.6 mmol) were added to a stirred solution of 3-(4-benzyloxy-benzofuran-7-yl)-2Z-ethoxy-acrylic acid ethyl ester (0.8 g, 2.18 mmol) in methanol (26 ml) and THF (13 ml) at ambient temperature. The suspension was warmed to 40° C. until evolution of hydrogen commenced. Then, the heating bath was replaced by a water bath, additional magnesium turnings (1 g, 41.2 mmol) were added and stirring of the reaction mixture was continued for 12 h. The suspension was cooled to 0° C., then 25% aqueous hydrochloric acid was added till all the solid had dissolved. The mixture was extracted twice with ethyl acetate and the combined ethyl acetate solutions were washed three times with water and dried over sodium sulfate. The solvent was evaporated to afford the title compound (0.77 g, 2.16 mmol, 99%) which was used in the next stage without further purification.
Reaction SMILES: C(N([C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][NH:12]2)=[CH:8][N:7]=1)CC)C.[F:15][C@@H:16]1[C@@H:20]([CH2:21][OH:22])[O:19][C@@H:18](N2C=CC(=O)NC2=O)[CH2:17]1.[N-]=[N+]=[N-].[K+].[C@@H:35]1([N:43]2[CH:51]=[C:49](C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)[CH2:36]1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[F:15][C@@H:16]1[C@@H:20]([CH2:21][OH:22])[O:19][C@@H:18]([N:12]2[CH:11]=[N:10][C:9]3[C:13]2=[N:14][CH:6]=[N:7][C:8]=3[N:43]([CH2:51][CH3:49])[CH2:35][CH3:36])[CH2:17]1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCN(CC)c1ncc2nc[nH]c2n1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=[N-]
Solvent: CO
Product: CCN(CC)c1ncnc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 264 h
Yield: 46 %

Procedure:
6 Diethylamino-9H-purine (0.50 g, 2.6 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.72 g, 3.2 mmoles) were suspended in 50 ml, 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 11 days, 150 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (9:1). Solvent was removed and lyophilization yielded 0.372 g of 9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-diethylamino-9H-purine (46%): mp 114°-115° C.; TLC Rf 0.70 (silica gel, MeCN:15N NH4OH:H2O/85:5:10);
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N+:11]#[C-:12].[N-:13]=[N+:14]=[N-:15].[Na+].O>C(#N)C.C(OCC)(=O)C>[CH3:12][N:11]1[C:10]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:15][N:14]=[N:13]1
Reactant: O=C(Cl)c1ccccc1
Reactant: [C-]#[N+]C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cn1nnnc1C(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
At room temperature, 10 g of benzoyl chloride (71 mmol) were admixed with 3.7 g (92 mmol) of methyl isocyanide. The mixture was then heated at 60° C. for 2 hours. The mixture was admixed with 25 ml of acetonitrile and cooled to 0° C. This reaction mixture was added to 4.6 g of sodium azide (71 mmol) in 25 ml of acetonitrile at 0° C. The mixture was then heated to 60° C. to 65° C. and stirred at this temperature for 16 hours. At room temperature, 100 ml of water and 100 ml of ethyl acetate were added to the mixture. The organic phase was separated off and the aqueous phase was extracted with 100 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and the solvent was removed in vacuo. The crude product could be recrystallized from 20 ml of isopropanol, giving 8.7 g of 1-methyl-5-benzoyltetrazole (purity 99.4%). This corresponds to a yield of 65%, based on the acid chloride used.
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[CH:13]=[C:12]([NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])[C:11]([CH3:22])=[CH:10][C:9]=1[CH3:23])(=[O:7])=[O:6])[C:2]#[CH:3].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32].[O:35]1CC[CH2:37][CH2:36]1>>[C:31]([N:4]([CH2:1][C:2]#[CH:3])[S:5]([C:8]1[CH:13]=[C:12]([N:14]([C:36](=[O:35])[CH3:37])[S:15]([C:18]([F:20])([F:21])[F:19])(=[O:16])=[O:17])[C:11]([CH3:22])=[CH:10][C:9]=1[CH3:23])(=[O:6])=[O:7])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: C#CCNS(=O)(=O)c1cc(NS(=O)(=O)C(F)(F)F)c(C)cc1C
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCN(C(C)=O)S(=O)(=O)c1cc(N(C(C)=O)S(=O)(=O)C(F)(F)F)c(C)cc1C
Reaction time: 8 h

Procedure:
To a solution of N-propargyl-2,4-dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonamide (1.5 g) and triethylamine (1.2 g) in tetrahydrofuran (20 ml), acetyl chloride (1.0 g) was added, and the resultant mixture was allowed to stand at room temperature overnight. The reaction mixture was concentrated, admixed with 5% hydrochloric acid and extracted with chloroform. The extract was concentrated to give an oily substance, which was purified by silica gel chromatography to give 1.4 g of N-acetyl-N-propargyl-2,4-dimethyl-5-(N-acetyl-N-trifluormethanesulfonylamino)benzenesulfonamide (Compound No. 75). nD20 1.5209.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][CH3:14])[CH2:11][C@H:10]([OH:15])[C@@H:9]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O>ClCCl.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][CH3:14])[CH2:11][C:10](=[O:15])[C@@H:9]1[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H]1C[C@H](O)[C@H](Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC[C@@H]1CC(=O)[C@H](Cc2ccccc2)N1C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 71.2 %

Procedure:
To a solution of (2S,3S,5R)-2-benzyl-5-ethyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.138 mmol; 42 mg) in dichloromethane (1.4 mL) is added Dess-Martin periodinane (0.166 mmol; 70.4 mg) at 0° C. The mixture is stirred at the same temperature for 1.5 hours. To the mixture, brine and EtOAc are added. The organic layer is separated, washed with saturated aqueous Na2S2O3 solution, dried over Na2SO4, filtered, concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; n-hexane/EtOAc) to give (2S,5R)-2-benzyl-5-ethyl-3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (29.8 mg, 71%); ESI-MS m/z: 248 [M+−tBu+2], Retention time 2.49 min (condition A).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:21]([CH3:23])[CH3:22])[CH:8]=2)[N:3]=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:1]([C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[C:2]2[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N:21]([CH3:23])[CH3:22])[CH:8]=3)[N:3]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN(C)c1ccc2nc(N)c(C#N)c(NCc3ccco3)c2c1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N(C(=O)c2ccc(OC)cc2)c2nc3ccc(N(C)C)cc3c(NCc3ccco3)c2C#N)cc1
Temperature: 0 °C

Procedure:
To the solution of 0.4 g of 2-amino-3-cyano-4-[2-furylmethylamino]-6-dimethylaminoquinoline in 2 mL of pyridine, 0.4 mL of 4-methoxybenzoyl chloride is added under stirring and cooling. The reaction mixture is stirred at 80° C. for 8 hours, then poured onto 5 mL of ice-water. The precipitated material is filtered off, washed twice with 3 mL of water. After drying 0.5 g of the title compound is obtained, m.p.: 143° C.
Reaction SMILES: [CH3:1][C:2]1([C:8](OCC)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C1(C)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(CO)CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 100-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl 4-methyltetrahydro-2H-pyran-4-carboxylate (compound 188.1, 500 mg, 2.90 mmol) in tetrahydrofuran (12 mL). This was followed by the addition of lithium aluminum hydride (221 mg, 5.82 mmol) in portions at 0° C. The reaction mixture was stirred for 1 h at room temperature, then carefully quenched with 1.2 mL of H2O, 1.2 mL of NaOH (15%), 3.5 mL of H2O. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. This resulted in 300 mg (crude) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([C@@H:22]([N:25](C)[C:26](=O)OC(C)(C)C)[CH2:23][CH3:24])=[CH:18][CH:17]=2)=[C:4]([O:34]C)[CH:3]=1.BrB(Br)Br>>[ClH:1].[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([C@@H:22]([NH:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)=[C:4]([OH:34])[CH:3]=1
Reactant: CC[C@@H](c1ccc(-c2c(OC)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1)N(C)C(=O)OC(C)(C)C
Agent: BrB(Br)Br
Product: CC[C@H](NC)c1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Yield: 45 %

Procedure:
Following General Procedure F, (S)-tert-butyl 1-(4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propyl(methyl)carbamate (100 mg, 0.194 mmol was reacted with tribromoborane (1.0 M in methylene chloride 1.2 mL, 1.16 mmol) to afford the desired product (35 mg, 45%) as a white solid: 1H NMR (500 MHz, DMSO) δ 10.81 (d, J=10.5 Hz, 1H), 9.83 (s, 1H), 9.70-9.45 (m, 1H), 9.28 (s, 1H), 7.73 (d, J=5.4 Hz, 1H), 7.70-7.60 (m, 2H), 7.38 (dd, J=12.4, 4.7 Hz, 3H), 5.70 (d, J=5.4 Hz, 1H), 4.19 (dt, J=12.1, 6.0 Hz, 1H), 2.51 (s, 3H), 2.20 (ddd, J=14.4, Z
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[NH:15][N:14]=[N:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:12][C:10]1[N:11]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:7]2[N:15]=[N:14][N:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]=2[N:9]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nnc2c(-c3ccco3)nc(N)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (101 mg, 0.5 mmol) in DMF (4 mL) was treated with 4-(N,N-dimethylamino)pyridine (5 mg, 0.04 mmol) and ethyl bromoacetate (55 mL, 0.5 mmol), stirred at room temperature for 16 h and purified directly by chromatography [SiO2; EtOAc:Heptane (1:2)] to give the title compound (50 mg, 35%) as a white solid.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][N:13]([CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22])[CH3:14].[Cl-:29].[NH4+]>CCOCC>[ClH:29].[CH3:14][N:13]([CH:15]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1([CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:22])[CH3:12]
Reactant: [Cl-]
Reactant: BrCCCc1ccccc1
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)CCCc1ccccc1
Product: Cl
Temperature: 25 °C
Yield: 67.7 %

Procedure:
0.32 g (13.0 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.58 g (13.0 mmole) of 1-bromo-3-phenylpropane dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at,RT. 2.50 g (10.8 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.73 g of crude base (98.2% of theory) were obtained, from which 2.92 g of 2-(dimethylaminophenylmethyl)-1-(3-phenylpropyl)cyclohexanol hydrochloride (67.7% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 90° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[OH:25][CH2:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[CH2:20]([N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:31]=[N:32][C:27]([CH2:26][OH:25])=[CH:28][CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:24])[C:13]2=[O:23])[C:16]([CH3:22])=[N:17]1)[CH3:21]
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Reactant: OCc1ccc(B(O)O)cn1
Product: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5ccc(CO)nc5)cc4c32)c(C)n1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 80 mg, 0.207 mmol) and 6-(hydroxymethyl)pyridine-3-boronic acid (Combi-Blocks, San Diego, USA, 39 mg, 0.254 mmol) to give the title compound as a white solid. (HPLC: tR 2.04 min (Method A); M+H=415 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.61-8.56 (m, 1H), 8.21-8.17 (m, 1H), 8.15-8.09 (m, 1H), 7.97-7.93 (m, 1H), 7.90-7.85 (m, 1H), 7.57-7.49 (m, 2H), 5.47 (t, 1H), 4.61-4.55 (m, 2H), 4.23-4.14 (m, 2H), 3.57 (s, 3H), 1.95 (s, 3H), 1.43 (t, 3H))
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.[C-:26]#[N:27].[Na+].[CH3:29][O:30][C:31]([C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)=[O:32]>>[CH3:29][O:30][C:31]([C:33]1[CH:39]=[CH:38][C:36]([NH:37][C:11]2([C:26]#[N:27])[CH2:10][CH2:9][N:8]([C:7]3[CH:6]=[CH:5][C:4]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:3][C:2]=3[F:1])[CH2:13][CH2:12]2)=[CH:35][CH:34]=1)=[O:32]
Reactant: [C-]#N
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: COC(=O)c1ccc(N)cc1
Agent: [Na+]
Product: COC(=O)c1ccc(NC2(C#N)CCN(c3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)CC2)cc1
Yield: 44 %

Procedure:
By using procedure as described in Example 45 and by reacting (S)—N-{3-[3-fluoro-4-(4-oxo-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with sodium cyanide and 4-methoxycarbonylaniline the compound was obtained in 44% yield.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7][NH:6][C:5](=O)[CH2:4][CH2:3]1.O1CCCC1.B.Cl>O1CCCC1>[NH3:6].[CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:3][CH2:4][CH2:5][NH:6][CH2:7]1
Reactant: CC1(c2ccccn2)CCC(=O)NC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC1(c2ccccn2)CCCNC1
Product: N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a dried flask under nitrogen was added borane tetrahydrofuran complex (1 M solution, 8.79 ml, 8.79 mmol), and tetrahydrofuran (10 ml). The solution was cooled to 0° C. and a solution of 5-methyl-5-(2-pyridinyl)-2-piperidone (Preparation 41, 1 g, 5.26 mmol) in tetrahydrofuran (20 ml) was added. The reactants were warmed to room temperature and then heated at reflux for 6 h. Further borane tetrahydrofuran, complex (1M solution, 8.79 ml, 8.79 mmol) was added and the reaction mixture was heated at reflux for 18 h. Thin layer chromatography still showed starting material was present so further borane tetrahydrofuran complex (1M solution, 8.79 ml, 8.79 mmol) was added and the reaction mixture was heated under reflux for 18 h. Upon completion hydrochloric acid (6M) was added to the reaction mixture and the mixture was stirred for 30 min. The reaction mixture was partially concentrated before adjusting to pH 11 with solid sodium hydroxide. The organic extracts were extracted with dichloromethane (5×20 ml) and dried (Na2SO4) to give a crude oil (0.45 g). The oil was purified by flash chromatography eluting with dichloromethane:methanol:0.88 ammonia solution (94:4:2) to give the title compound as an oil (0.20 g, 22%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Br:9])=[CH:6][CH:5]=1.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[Br-:9].[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][P+:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:6][CH:5]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Solvent: CC#N
Product: FC(F)(F)Oc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]

Procedure:
A solution of 4-(trifluoromethoxy)benzyl bromide (5.3 g) and triphenylphosphine (5.42 g) in acetonitrile (100 ml) was heated under reflux for 12h. The acetonitrile was evaporated under reduced pressure, and ethyl acetate (50 ml) was added to the residue. The solid material so obtained was filtered off, washed with ethyl acetate (100 ml) and dried, to give (4-trifluoromethoxybenzyl)triphenyl phosphonium bromide, N.M.R. in d6 -dimethylsulphoxide: δ5.2 (2H,d), 7.1 (2H,2d), 7.25 (2H,d), 7.8 (9H,m).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@:5]1([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6]1)[CH3:2].[ClH:36]>CCOCC>[ClH:36].[ClH:36].[CH2:1]([O:3][CH2:4][C@:5]1([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:9][CH2:8][C@@H:7]([NH2:10])[CH2:6]1)[CH3:2]
Reactant: CCOC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CCC(NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Product: CCOC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl [(3S)-3-(ethoxymethyl)-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (295 mg, 0.589 mmol) was dissolved in a 2 M solution of hydrogen chloride in ether (10 mL). After being stirred at room temperature overnight, the reaction mixture was concentrated under vacuum to provide the desired product (330 mg) as a light yellow solid. MS calculated for C19H28F3N4O2: (M+H) 401.3; found 401.3.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([OH:16])[C:14]#[CH:15].C=O.O.[CH:20](Cl)(Cl)[Cl:21]>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[ClH:21].[ClH:21].[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:20][C:15]#[C:14][CH2:13][OH:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCO
Reactant: ClC(Cl)Cl
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [Cu+2]
Agent: C=O
Agent: CC(=O)[O-]
Solvent: O
Product: Cl
Product: OCC#CCN1CCN(c2ccccc2)CC1

Procedure:
1-Phenylpiperazine (16.2 g; 0.10 mole) is weighed to propargyl alcohol (11.8 ml; 0.20 mole), copper(II) acetate monohydrate (1.0 g; 5.2 mmoles) is added to it, and 37% aqueous formaline (50 ml) is pipetted to the reaction mixture under stirring. The green suspension is refluxed for 2 hours. Then it is cooled, water and chloroform are added to it and the pale green substance insoluble in both phases are filtered off. The aqueous phase is extracted twice with chloroform, the combined organic phases are dried over sodium sulfate and evaporated. The residual brown oil is dissolved in ethyl acetate, and a solution of 2 molar equivalents of hydrogen chloride in ethyl acetate is dropped to it under stirring. The separated white salt is filtered off, digested while hot with isopropanol, cooled and filtered.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:2]3[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OB(O)c1ccc(OC2CCCCC2)nc1
Reactant: Cc1cnc(N)c(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1cnc(N)c(-c2ccc(OC3CCCCC3)nc2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (48.3 mg) was added to a suspension of 3-chloro-5-methylpyrazin-2-amine (200 mg), 6-(cyclohexyloxy)pyridin-3-ylboronic acid (339 mg) and sodium carbonate (295 mg) in DME (5 mL) and water (1 mL) and the mixture was stirred at 90° C. under nitrogen for 3 hr. Water and EtOAc were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (339 mg) as light brown gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]([OH:25])(=[O:24])[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=C.[CH2:26](O)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:26][C:18]2([CH2:16][C:15]([OH:25])=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH2:23]2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCO
Reactant: C=C(C(=O)O)c1ccccc1
Product: COc1ccccc1N1CCN(CC2(CC(=O)O)C=CC=CC2)CC1
Temperature: 25 °C

Procedure:
1-(2-Methoxyphenyl)piperazine (22.6 g, 0.118 mol) and atropic acid (174 g, 0.118 mol) in ethanol (300 ml) were heated under reflux for 18 hours, cooled to room temperature, and evaporated in vacuo. The solid was triturated with acetone (3×100 ml) to give a first crop of product (13.8 g) as white crystals. The filtrate was evaporated in vacuo to give an oil which slowly crystallised over 1 month. The solid was triturated with acetone (200 ml) to give a second crop of the hemihydrate of the product (9.01 g) as white crystals, m.p. 160°-163°.