Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:14]([O:16]CC)=[O:15])=[N:4][O:5][C:6]=1[CH:7]1[CH2:12][CH:11]=[CH:10][CH:9]([CH3:13])[O:8]1.[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][O:5][C:6]=1[CH:7]1[CH2:12][CH:11]=[CH:10][CH:9]([CH3:13])[O:8]1
Reactant: CCOC(=O)c1noc(C2CC=CC(C)O2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)noc1C1CC=CC(C)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 4-methyl-5-(6-methyl-3,6-dihydro-2H-pyran-2-yl)isoxazole-3-carboxylate (14 mg, 0.056 mmol) in MeOH (0.2 mL) and THF (0.3 mL) was added 2M NaOH (aq) (27.9 μl, 0.056 mmol). The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure and 2M NaOH (aq) (1 mL) and water (1 mL) added. The aqueous was extracted with DCM (×3) and the combined organic extracts passed through a phase separating cartridge. The eluent was concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](O)=[O:23])[CH:17]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:22]([C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)=[O:23])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 ml of a N,N-dimethylformamide solution containing 1 g of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine, 632 mg of 3-pyridinecarboxylic acid, 1.07 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide and 757 mg of 1-hydroxybenzotriazole was stirred at room temperature for 24 hours. To the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was washed with diethyl ether to obtain N-tert-butoxycarbonyl-trans-4-(3-pyridylcarbonylamino)cyclohexylamine. A mixture comprising 1.27 g of this compound and 13 ml of 15% hydrochloric acid-ethanol solution was stirred at 50° C. for 2 hours. After cooling, precipitates were filtered and washed with diethyl ether to obtain 1.12 g of trans-4-(3-pyridylcarbonylamino)cyclohexylamine.dihydrochloride (Reference Example-10-2 in Table 11).
Reaction SMILES: [Cl:1][C:2]1([C:5]([OH:21])([CH2:14][N:15]2[C:19]([SH:20])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1.[C:22](=O)([O-])[O-].[K+].[K+].CI.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1([C:5]([OH:21])([CH2:14][N:15]2[C:19]([S:20][CH3:22])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CC#N
Product: CSc1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1
Temperature: 40 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
A mixture of 3.43 g (10 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol, 20 ml of absolute acetonitrile and 1.38 g of (10 mmol) of potassium carbonate is treated with 0.93 ml (15 mmol) of methyl iodide and the mixture is stirred at 40° C. for 5 hours. The reaction mixture is then treated with saturated, aqueous sodium carbonate solution and extracted repeatedly using ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. In this manner, 3.4 g (95% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-methylthio-1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of oil.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH:18](Br)[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH:1]([N:14]1[CH2:19][CH2:18][CH:17]1[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Br)CCBr
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1CCN1C(c1ccccc1)c1ccccc1

Procedure:
Combine benzhydrylamine (27.5 g=0.15 ml), 1,3-dibromobutane (40.5 g=0.19 mol) and sodium carbonate (28 g=0.33 mol) in 250 ml acetonitrile. Reflux 24 hours, allow to cool, filter and concentrate. Dissolve the residue in ether and wash with 1% sodium carbonate solution. Dry, concentrate and distill to obtain the product, boiling point 110°-115° C./0.1 mm pressure.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:14]=2[CH3:21])[C:8](=[O:22])[CH:7]=1.[Cl:28]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:28][C:7]1[C:8](=[O:22])[N:9]([C:13]2[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:14]=2[CH3:21])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:2]=1[F:1]
Reactant: Cc1ccc(CO)cc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cc1ccc(CO)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared by a procedure similar to the one described for Example 481, except that the product from Step 2, Example 481 was chlorinated instead of being brominated. The procedure is as follows: 4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one (from Step 2, Example 481 above) (7.0 g, 18.8 mmol) was refluxed with N-chlorosuccinimide (2.5 g, 18.8 mmol) in 50 ml of CH2Cl2 overnight. The reaction was evaporated on a rotary evaporator and the resulting solid was stirred in MeOH. The precipitate was collected on a filter pad, washed with MeOH and dried in vacuo to yield a white solid (1.6 g, 21%). 1H NMR (300 MHz, DMF-d7) δ 7.85 (app q, J=6.44 Hz, 1H), 7.43 (d, J=0.81, 1H), 7.42-7.23 (m, 3H), 6.84 (s, 1H), 5.48 (s, 2H), 4.67 (s, 2H), 2.05 (s, 3H), 2.03 (s, 3H); ES-MS m/z 406 (M+H). ES-HRMS m/z 406.1033 (M+H calcd for C21H16ClF2NO4 requires 406.1016).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([NH2:48])=[O:47])=[CH:44][C:43]=1I.C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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.C(O)C.O1CCOCC1>[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([NH2:48])=[O:47])=[CH:44][C:43]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2
Reactant: Brc1ccc2c(N3CCOCC3)nncc2c1
Reactant: NC(=O)c1ccc(Cl)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(Cl)c(-c2ccc3c(N4CCOCC4)nncc3c2)c1
Temperature: 80 °C

Procedure:
To 6-Bromo-1-morpholinophthalazine (0.20 g, 680 μmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (50 mg, 68 μmol), potassium acetate (200 mg, 2040 μmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (207 mg, 816 μmol) was added 1,4-dioxane (6.80 mL) and the mixture was heated to 80° C. for 2 h. The mixture was added to a sealed tube containing 4-chloro-3-iodobenzamide (230 mg, 816 μmol), tetrakis(triphenylphosphine)palladium (79 mg, 68 μmol), potassium carbonate—1.5 M in water (1.81 μl, 2.72 mmol), and ethanol (6.80 mL) and heated to 110° C. for 2 h. After cooling the reaction mixture was diluted with 75 mL of ethyl acetate, added to a separation funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 3 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, concentrated in vacuo, and purified by HPLC to give the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[N:8]=[CH:7][C:6]=2[CH:5]=[CH:4]1)[CH3:2].C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl>[Br:23][C:5]1[C:6]2[CH:7]=[N:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:11]=2[N:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1ccc2cnc(C(=O)OC)cc21
Solvent: ClCCl
Product: CCn1cc(Br)c2cnc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To an ice-cooled solution of methyl 1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (IF, 700 mg, 3.43 mmol) in DCM (5 ml) was added NBS (610 mg, 3.43 mmol). The reaction mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated in vacuo and purified by chromatography (SiO2, EtOAc) to give methyl 3-bromo-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (3A, 950 mg, 3.36 mmol, 98% yield) as a white powder. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (t, J=7.33 Hz, 3 H) 4.04 (s, 3 H) 4.25 (q, J=7.33 Hz, 2 H) 7.33 (s, 1 H) 8.22 (d, J=0.76 Hz, 1 H) 8.92 (d, J=1.01 Hz, 1 H).
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[NH:13][CH2:14][CH2:15][NH2:16]>C(O)C>[CH3:12][C:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]([CH3:4])[C:6]=1[N:13]1[CH2:14][CH2:15][N:16]=[C:2]1[NH2:1]
Reactant: Cc1cc(C)c(NCCN)c(C)c1
Reactant: N#CBr
Solvent: CCO
Product: Cc1cc(C)c(N2CCN=C2N)c(C)c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A solution of cyanogen bromide (1.8 g, 18.5 mmol) in anhydrous ethanol (3 mL) was added at 0° C. to a solution of N1-(2,4,6-trimethyl-phenyl)-ethane-1,2-diamine (3.0 g, 16.9 mmol) in anhydrous ethanol (9 mL) under nitrogen. The reaction mixture was warmed up to room temperature for 10 min, then was heated at 155° C. for 40 min with a flow of nitrogen to remove ethanol. Upon cooling to r.t., the resulting solids were transferred to a separatory funnel via dichloromethane (70 mL), and washed sequentially with 1 N sodium hydroxide (2×35 mL), water and brine. The organic layer was dried over anhydrous sodium sulfate and solvents were removed in vacuo to afford the title compound as a pale white solid (3.08 g, 90% yield). The solids were used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([C:12]([NH2:14])=O)[O:8][C:7]=2[CH:15]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([C:12]#[N:14])[O:8][C:7]=2[CH:15]=1
Reactant: COc1ccc2c(c1)OC(C(N)=O)=CO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)OC(C#N)=CO2

Procedure:
1.76 g (8.52 mmol) of the amide obtained in Step A and 4.62 g (30 mmol) of phosphorus oxychloride are dissolved in 40 ml of anhydrous pyridine. The reaction medium is then heated at reflux for 1 hour under an inert atmosphere; the solvent is then evaporated in vacuo. The residue obtained is slowly hydrolysed with a saturated solution of sodium hydrogen carbonate; the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrate in vacuo. The title nitrile is obtained pure in the form of a white solid after passage over a silica column (eluant: AcOEt/PE: 10/60).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:8](Cl)([Cl:10])[Cl:9]>C(N(CC)CC)C>[O:7]([P:8]([Cl:10])[Cl:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: ClP(Cl)Cl
Solvent: CCN(CC)CC
Product: ClP(Cl)Oc1ccccc1

Procedure:
Further starting compounds HalPnR1R2 and HalPnR3R4 are obtainable by stepwise synthesis. Thus, for example, reaction of phenol with phosphorus trichloride in the presence of a tertiary amine, e.g. triethylamine, produces phenoxyphosphorus dichloride which can be reacted with one equivalent of the appropriate pyrrole compound, e.g. pyrrole, in the presence of a tertiary amine to give phenoxypyrrolylphosphorus chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21]OS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCOCC1>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(CCN3CCCC3)cc2c1C(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of 5-(2-methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (100 mg, 0.26 mmol) in dioxane (5 mL) was added pyrrolidine (0.2 mL, 2.6 mmol). The mixture was stirred at 70° C. for 1 hour and then was concentrated in vacuo to give a residue, which was purified by chromatography (5%-15% methanol in methylene chloride) to give 85 mg (91%) of the desired product as a thick oil: MS(APCI+): m/z 363.2 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH:5]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:7]=2[CH2:6]1.[OH-].[K+]>C(O)C.O>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:8]2[O:9][CH:5]([CH2:4][C:3]([OH:16])=[O:2])[CH2:6][C:7]=2[CH:13]=1
Reactant: COC(=O)CC1Cc2cc(OC)ccc2O1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CC(CC(=O)O)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
110 g of 5-methoxy-2,3-dihydro-3-benzofuranacetic acid methylester dissolved in 400 ml of ethanol were added during 20 minutes to a solution of 55 g of KOH in 70 ml of water and 500 ml of ethanol at reflux temperature. Reflux was continued for 0.5 hours. Ethanol was evaporated and 600 ml of water were added, and the mixture was acidified with cold conc. hydrochloric acid and subsequently extracted with dichloromethane (3×300 ml). The combined organic phases were washed with brine, dried (MgSO4) and evaporated to a volume of 200 ml. 700 ml of n-heptane were added, and excess dichloromethane evaporated. The mixture was cooled to 0° C., and the precipitated carboxylic acid filtered off. Yield: 91 g. M.P. 111°-112° C.
Reaction SMILES: [C:1]1([C:7]2[C:11]3=[N:12][C:13](=[O:16])[C:14](=[O:15])[C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:23]([N:12]1[C:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:9]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]=2[C:14](=[O:15])[C:13]1=[O:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1nc2c(-c3ccccc3)c(-c3ccccc3)nc-2c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccccc2)c2c(-c3ccccc3)c(-c3ccccc3)n(Cc3ccccc3)c21
Temperature: 100 °C
Yield: 101.3 %

Procedure:
A 100 ml round-bottom flask equipped with a stirrer and reflux condenser is charged with 1.47 g (5.1 mmol) of diphenyl-diketopyrrolopyrrole (hereinafter referred to DPP), 3.44 g (20.1 mmol) of benzyl bromide, 1.38 g (10.0 mmol) of K2CO3 and 50 ml of DMF. Under nitrogen atmosphere, the mixture is stirred and heated at 100° C. for 42.5 hours. The slurry is cooled and the orange solid is isolated by filtration. The solid is washed with water and MeOH, followed by dissolving in hot CHCl3. This CHCl3 solution is applied to silica gel column using CH2Cl2 as eluent. After condensation, 1.21 g of an orange solid is obtained (51%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:26][CH:27]1CC1.[C-]#N.[K+]>>[Br:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH:20]3[CH2:27][CH2:26]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CC1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Agent: [C-]#N
Agent: [K+]
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Reaction time: 1.5 h

Procedure:
A mixture of 12 g (31 mmol) of ethyl (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 60 ml (750 mmol) of hydroxymethyl-cyclopropane and 500 mg of powdered potassium cyanide is stirred at 135° for 1.5 hours, the alcohol being simultaneously distilled off over a Hickmann headpiece and a 15 cm Vigreux column. The mixture is evaporated to dryness, the residue is taken up in chloroform, washed with water, dried over magnesium sulphate and evaporated. By recrystallization from ethyl acetate there is obtained cyclopropylmethyl (S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 135°-136°.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH2:13][F:14])[CH2:11][O:10][C:9]2=[O:15])[C:5]([F:16])=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][C:27]([C@@H:29]([NH2:31])[CH3:30])=[N:26][CH:25]=2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[O:28][C:27]([C@@H:29]([NH:31][C:2]3[N:7]=[C:6]([N:8]4[C@@H:12]([CH2:13][F:14])[CH2:11][O:10][C:9]4=[O:15])[C:5]([F:16])=[CH:4][N:3]=3)[CH3:30])=[N:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: O=C1OC[C@H](CF)N1c1nc(F)ncc1F
Reactant: C[C@H](N)c1ncc(-c2ccc(Cl)cc2)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2CF)n1)c1ncc(-c2ccc(Cl)cc2)o1
Temperature: 120 °C
Yield: 86.4 %

Procedure:
(R)-3-(2,5-difluoropyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one (105 mg, 0.449 mmol), (S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethanamine (100 mg, 0.449 mmol), and DIPEA (157 ul, 0.898 mmol) were dissolved in DMSO (1 mL) and the reaction mixture was heated at 120° C. for 2 h. The reaction mixture was cooled, diluted with EtOAc, washed with water and brine, and concentrated in vacuo. Column chromatography (5-50% EtOAc/DCM) gave the desired product (169 mg) as a white foam. 1H NMR (400 MHz, CDCl3) b 8.26 (d, J=2.8 Hz, 1H), 7.59-7.50 (m, 2H), 7.45-7.36 (m, 2H), 7.25 (s, 1H), 5.66 (d, J=7.6 Hz, 1H), 5.21 (br s, 1H), 4.86 (ddddd, J=20.0, 8.6, 7.0, 4.3, 2.8 Hz, 1H), 4.66-4.44 (m, 3H), 4.41 (br s, 1H), 1.71 (d, J=7.0 Hz, 3H). HRMS-Acidic. LC-UV/ESI-MS data was recorded on an Acquity LCTp Tof—Rs(FWHM) >12000 Accuracy <5 ppm. Column: Acquity BEHC18 1.7 μm 2.1×50 mm-50° C.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=4[CH:16]=3)[CH2:8][CH2:7]2)=O)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH2:4][N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=4[CH:16]=3)[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: O=C(C1CC1)N1CCC(c2cc3ccccc3o2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2oc(C3CCN(CC4CC4)CC3)cc2c1

Procedure:
A solution of 14.5 g of 1-(cyclopropylcarbonyl)-4-(2-benzofuranyl)-piperidine in 100 ml of tetrahydrofuran is added dropwise to a refluxing solution of 13.5 g of lithium aluminium hydride in 200 ml of tetrahydrofuran. After 15 hours' refluxing, the reaction mixture is cooled, and the excess lithium aluminium hydride broken down at -10° by means of 15 ml of water, 15 ml of 10% sodium hydroxide solution and 45 ml of water. The reaction solution is filtered off under suction and the filter residue subsequently washed with 1 liter of chloroform; the combined filtrates are then concentrated in vacuo. The residue is dissolved in 500 ml of 2 N hydrochloric acid, and the acid solution washed with ether. The aqueous solution is thereupon adjusted by addition of 10% sodium hydroxide solution to pH 12, and extracted with 1 liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered off with suction, and concentrated by evaporation to obtain crude 1-(cyclopropylmethyl)-4-(2-benzofuranyl)-piperidine. After recrystallisation from hexane, the free base melts at 68°. The hydrochloride is prepared with hydrogen chloride in ethyl acetate, and recrystallised from ethyl acetate, whereupon it melts at 223°-225°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([F:11])[C:5]([CH3:12])=[CH:4][CH:3]=1.C(Cl)Cl.C(Cl)(=O)C(Cl)=O.C[N:23](C=O)C>>[Cl:1][C:2]1[C:7]([C:8]([NH2:23])=[O:9])=[C:6]([F:11])[C:5]([CH3:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)c(C(=O)O)c1F
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(Cl)c(C(N)=O)c1F

Procedure:
To 6-chloro-2-fluoro-3-methylbenzoic acid (10 g, 53 mmol) is added CH2Cl2 (60 mL), DMF (0.5 mL) and oxalyl chloride (9.25 mL, 106 mmol). The reaction mixture is allowed to stir until it reaches homogeneity and is then concentrated in vacuo. The residue is poured onto a 50:50 mixture of ice and 36% ammonium hydroxide to yield 6-chloro-2-fluoro-3-methylbenzamide.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:6]([C:16]2[N:17]=[C:18]([NH2:24])[NH:19][C:20](=[O:23])[C:21]=2[N:22]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])[CH:2]=[CH2:3].[CH2:25](Br)C=C>>[CH2:1]([S:4][C:5]1[N:6]([C:16]2[N:17]=[C:18]([NH2:24])[NH:19][C:20](=[O:23])[C:21]=2[N:22]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])[CH:2]=[CH:3][CH3:25]
Reactant: C=CCBr
Reactant: C=CCSc1nc2c(=O)[nH]c(N)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: CC=CCSc1nc2c(=O)[nH]c(N)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 48 %

Procedure:
Following the first procedure for the preparation of 8-(2-propenylmercapto)guanosine (Example 9), but substituting 2-butenyl chloride for allyl bromide, the title compound was obtained in 48 percent yield as a white powder, mp 210° C. (decomp.). NMR (DMSO-d6): δ 6.3 (bs, 2H); 5.6 (d, J=5 Hz 1H); 1.6 (d, J=6 Hz 3H). IR (KBr): 1690, 1630, 1600, 1510 and 1365 cm-1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].C(O)C.[Na].C(O)(=O)C>C(Cl)Cl.O>[OH:12][CH:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=C1CCCC1c1ccccn1
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: OC1CCCC1c1ccccn1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
In an argon gas stream atmosphere, 80.0 g (496 mM) of 2-(2-pyridyl)cyclopentanone and 1600 ml of dry ethanol were placed in a 2 liter-three-necked flask, followed by stirring at room temperature and then addition thereto of 18.7 g (496 mM) of sodium boronhydride. The system was then stirred for 2 hours at room temperature, followed by addition thereto of a small amount of acetic acid and water. The reaction mixture was methylene chloride. The organic layer was dried with anhydrous sodium sulfate and subjected to distilling-off of the solvent under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain 61.0 g of 1-hydroxy-2-(2-pyridyl)cyclopentane (Yield: 75.3%)