Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([OH:8])=O)[CH3:2].O1CCCC1.[F:17][C:18]([F:25])([C:21]([F:24])([F:23])[F:22])[CH2:19][NH2:20].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([NH:20][CH2:19][C:18]([F:25])([F:17])[C:21]([F:24])([F:23])[F:22])=[O:8])[CH3:2]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: CCOC(=O)C(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)C(=O)NCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of 2.08 g (12.8 mmol) 2-hydroxy-2-methyl-malonic acid monoethyl ester in 50 ml of tetrahydrofuran 1.39 g (12.8 mmol) of 2,2,3,3,3-pentafluoropropylamine, 2.51 g (12.8 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 1.77 g (12.8 mmol) of 1-hydroxybenzotrizole hydrate and 4.48 ml (25.7 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. Silicagel was added and the solvent was removed by distillation. The residue was purified by chromatography on silicagel (ethyl acetate/heptane=0:100 to 50:50) to yield 3.01 g (80%) of the title compound as white solid, MS m/e (%): 292.1 (M−H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[N:15][C:14]=3[C:13]([C:20](O)=[O:21])=[CH:12][CH:11]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1.Cl.[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)[CH2:29][CH2:28]1)[CH3:26]>>[CH2:25]([N:27]1[CH2:28][CH2:29][N:30]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:20]([C:13]3[C:14]4[N:15]=[CH:16][CH:17]=[N:18][C:19]=4[C:10]([C:5]4[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=4[CH3:23])=[CH:11][CH:12]=3)=[O:21])=[N:38][CH:39]=2)[CH2:31][CH2:32]1)[CH3:26]
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Reactant: COc1cc(C)cc(-c2ccc(C(=O)O)c3nccnc23)c1C
Agent: Cl
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(C)cc(OC)c4C)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(3-methoxy-2,5-dimethyl-phenyl)quinoxaline-5-carboxylic acid (Step 97.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Step 26.1) and stirring the reaction mixture for 24 h at rt. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1). Title compound: ESI-MS: 511.1 [M+H]+; tR=3.75 min (System 1); TLC: Rf=0.29 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[CH:8]2)=[O:4].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.O1CCOCC1>CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:20][C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(ccn2C)c1
Reactant: Fc1ccc(CBr)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(F)cc1)cn2C
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A solution of 1-methyl-1H-indole-5-carboxylic acid methyl ester (0.17 g, 0.9 mmol), prepared using procedures as described in Example 1, Ag2O) (0.22 g, 0.95 mmol), 4-fluoro-benzyl bromide (0.18 g, 0.95 mmol) and dioxane (4 mL) were heated to reflux for 16 hr, then more 4-fluoro-benzyl bromide (90 mg, 0.5 mmol) was added and the solution was heated at reflux an additional 4 hr. After cooling to room temperature, the reaction mixture was diluted with ether (60 mL), washed with aq. NH4Cl (50 mL) and then brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 1:3) to provide 3-(4-fluoro-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid methyl ester (58 mg, 22% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C([Li])CCC.CN(OC)[C:23](=[O:25])[CH3:24]>C1COCC1>[F:15][C:14]1[CH:13]=[CH:12][C:4]([CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)=[CH:3][C:2]=1[C:23](=[O:25])[CH3:24]
Reactant: Fc1ccc(CN2CCOCC2)cc1Br
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1cc(CN2CCOCC2)ccc1F
Temperature: -75 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
A solution of 4-(3-bromo-4-fluorobenzyl)morpholine (35.5 g) of Preparation No. 53 in THF (400 mL) is cooled to −75° C., and n-butyllithium is added via addition funnel maintaining the temperature below −65° C. A solution of N-methyl-N-methoxyacetamide (16.0 g, prepared as described in Tetrahedron Lett. 1983, 24, 1857) in THF (50 mL) is added via addition funnel, again maintaining temperature below −65° C. The reaction is stirred at −75° C. for 1 hour and then is allowed to warm to room temperature overnight. The reaction mixture is quenched with 1 N HCl (150 mL) and diluted with ethyl acetate (400 mL). The layers are separated, and the aqueous layer is basified with sat. sodium bicarbonate solution. The aqueous layer is extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with sat. sodium bicarbonate (2×100 mL) and brine (50 mL). The aqueous layers are back-extracted with ethyl acetate (100 mL). The combined organic layers are dried (Na2SO4) and concentrated in vacuo to a yellow oil. The oil is purified by fractional distillation at 135-140° C./0.3 torr to afford 19.7 g (64%) of the title compound as a clear, colorless oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])C1C=CN=C(S)C=1.[C:12]([O-:15])([O-])=[O:13].[K+].[K+].CN(C=[O:22])C>CC#N>[C:12]([OH:15])([C:2]([F:11])([F:10])[F:1])=[O:13].[OH2:22].[C:12]([OH:15])([C:2]([F:11])([F:10])[F:1])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1ccnc(S)c1
Reactant: CN(C)C=O
Agent: [K+]
Solvent: CC#N
Product: O
Product: O=C(O)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Glucose-C6-2-mesitylenesulfonated vancomycin TFA salt (XLI) (10 mg, 0.00573 mmol), 4-(trifluoromethyl)-2-pyridinethiol (21.6 mg 0.12 mmol), and K2CO3 (17 mg 0.123 mmol), are dissolved with dry DMF (0.5 mL). The mixture is stirred at 65° C. After 2 h. analytical HPLC indicates the reaction is done. The mixture is filtered and purified by ODS-HPLC (LUNA 5 μm C18(2), 21.2×250 mm, UV=285 nm, A: 0.1% TFA/H2O, B: MeCN, 0-50-100% B 0-30-40 min., 8 mL/min, tr=35 min.) to give (LX) as a white amorphous TFA salt (2.3 mg, 0.00133 mmol, 23%). LRESI-MS 1613 (M+4H, for C71H8035Cl2F3N11O23S)+, 1143 (M-vancosamine-glucose+H)+.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[N:17][CH:18]=1.[C:20](=O)([O-])[OH:21].[Na+]>CN(C=O)C.C(OCC)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH:20]=[O:21])=[CH:18][N:17]=1
Reactant: O=C([O-])O
Reactant: Clc1ccc(Br)cn1
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1ccc(Cl)nc1

Procedure:
At −78° C., a hexane solution (11.5 mL) of 1.59 M n-butyllithium was dropwise added to a diethyl ether solution (140 mL) of 5-bromo-2-chloropyridine (2.9 g). This was stirred at that temperature, then a diethyl ether solution (3 mL) of DMF (1.8 mL) was added thereto and stirred at that temperature for 3.5 hours. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate/hexane=1/9) to obtain the entitled compound (1.4 g).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.C([O-])(=O)C.[NH4+:13]>CO>[C:1]([OH:7])(=[O:6])[CH3:2].[NH2:13][C@H:3]([CH3:5])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: [NH4+]
Reactant: COC(=O)CC(C)=O
Agent: CC(=O)[O-]
Solvent: CO
Product: CC(=O)O
Product: COC(=O)C[C@@H](C)N
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Ru(OCOCH3)2((R)-dm-binap) (164.3 mg, 0.1722 mmol), methyl acetoacetate (10.00 g, 86.12 mmol), ammonium acetate (6.64 g, 86.12 mmol) and methanol (50 mL) were placed in a stainless steel autoclave under nitrogen atmosphere, and the mixture was stirred at 80° C. under a hydrogen pressure of 3 MPa for 15 hours. After completion of the reaction, the solvent was removed by evaporation to give methyl (3R)-3-aminobutanoate acetate as a crude material (16.29 g). The crude product was treated with 7N ammonia/methanol and analyzed by GLC analysis using a capillary column TC-5HT (available from GL SCIENCES CO.), indicating that the yield of methyl 3-aminobutanoate was 86.4%, that of the by-produced methyl 3-hydroxybutanoate was 0.7%, that of the by-produced methyl 3-aminocrotonate was 1.4% and that of the by-produced methyl 3-(2-methoxycarbonyl-1-methyl-ethylamino)-2-butenoate was 6.2%. The enantiomeric excess of methyl (3R)-3-aminobutanoate in the crude product was found to be 81.9% ee by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3-(4-nitrobenzoylamino)butanoate.
Reaction SMILES: [N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][CH:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:8]3.[C:17](Cl)([Cl:19])=[O:18].C(N(CC)CC)C>ClCCl.C1C=CC=CC=1>[N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][CH:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:8]3[C:17]([Cl:19])=[O:18]
Reactant: c1ccc2c(c1)NC1CCCc3onc-2c31
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Cl)N1c2ccccc2-c2noc3c2C1CCC3

Procedure:
In 50 ml of dichloromethane was dissolved 4.08 g of 4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine. Phosgene in benzene (26 ml of 12.5% phogene in benzene) was then added all in one portion. This solution was then chilled with an ice/water bath as a solution of triethylamine (2.92 g) in 20 ml of dichloromethane was added dropwise. After the addition was complete (30 minutes), the reaction mixture was washed with dilute hydrochloric acid and then dried and concentrated. The residue obtained in this manner was recrystallized from dichloromethane/hexane to give 3.66 g of product, m.p. 189° C. (d).
Reaction SMILES: O1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)[CH2:3][CH2:2]1.C1[CH:53]2CCC[CH:52]2[CH2:51]N1>>[CH2:3]1[CH:2]2[CH2:51][CH2:52][CH2:53][CH:6]2[CH2:5][N:4]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=2)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]2[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:46])[F:47])[CH:39]=3)[CH:32]=[CH:31][N:30]=2)[CH:8]=1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: C1CC2CNCC2C1
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CC4CCCC4C3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of 3-((3-((4-morpholino-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-carbamoyl)benzyl)thio)propanoic acid 14, using octahydrocyclopenta[c]pyrrole in place of morpholine. 1H-NMR (300 MHz, DMSO-d6+D2O, ppm): δ 9.54 (s, 1H), 8.92 (d, J=3 Hz, 1H), 8.25 (s, 1H), 8.11 (d, J=9 Hz, 1H), 7.73 (m, 2H), 7.58 (m, 2H), 7.49 (m, 2H), 7.45 (m, 2H), 7.02 (s, 1H), 6.80 (d, J=9 Hz, 1H), 4.60 (s, 2H), 3.84 (s, 2H), 3.05 (d, J=6 Hz, 2H), 2.77 (m, 2H), 2.56 (m, 3H), 1.80 (m, 2H), 1.52 (m, 3H). MS (ES, m/z): 703 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[C:5]12([CH2:14][CH:13]([N:15]3[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=[CH:16]3)[C:12]3[CH:24]=[CH:25][CH:26]=[CH:27][C:11]=3[O:10]1)[CH2:9][CH2:8][CH2:7][CH2:6]2.CO.[Br:30]Br>O>[N+:1]([O-:4])([OH:3])=[O:2].[Br:30][C:25]1[CH:26]=[CH:27][C:11]2[O:10][C:5]3([CH2:9][CH2:8][CH2:7][CH2:6]3)[CH2:14][CH:13]([N:15]3[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=[CH:16]3)[C:12]=2[CH:24]=1
Reactant: BrBr
Reactant: COC(=O)c1cncn1C1CC2(CCCC2)Oc2ccccc21
Solvent: O=[N+]([O-])O
Solvent: CO
Solvent: O
Product: COC(=O)c1cncn1C1CC2(CCCC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
To a stirred solution of 6.0 parts of methyl 1-[3,4-dihydrospiro-[2H-1-benzopyran-2,1'-cyclopentan]-4-yl]-1H-imidazole-5-carboxylate mononitrate in 135 parts of methanol were added 3.2 parts of bromine. The mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into water and the whole was made alkaline. The product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated. The residue was converted into the nitrate salt in a mixture of 16 parts of 2-propanone and 40 parts of 2,2'-oxybispropane. The salt was filtered off and dried in vacuo, yielding 4.4 parts (48.4%) of methyl 1-(6-bromo-3,4-dihydrospiro-[2H-1-benzopyran-2,1'-cyclopentan]-4-yl)-1H-imidazole-5-carboxylate mononitrate; mp. 162.3° C. (compound 1.63).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[C:9]([CH2:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][C:9]1[O:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:20])([F:29])[F:30])=[CH:23][CH:24]=3)[C:3]=2[N:10]=1
Reactant: Clc1cccc(Cl)c1Cc1nc2c(Cl)ncnc2o1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(Nc2ncnc3oc(Cc4c(Cl)cccc4Cl)nc23)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A mixture of 7-chloro-2-(2,6-dichloro-benzyl)-oxazolo[5,4-d]pyrimidine (42 mg, 0.13 mmol), 4-trifluoromethyl-phenylamine (22 mg, 0.13 mmol), and p-TsOH.H2O (51 mg, 0.27 mmol) in toluene (2 mL) was heated to 120° C. in a sealed tube. After 2 h, the solution was cooled purified by preparative reverse-phase HPLC to afford the title compound as a colorless solid (20 mg, 34%). MS (ESI): mass calcd. C19H11Cl2F3N4O, 438.0; m/z found, 439.1 [M+H]+. 1H NMR (CDCl3): 8.57 (s, 1H), 7.90 (d, J=8.6 Hz, 2H), 7.76 (s, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.31-7.27 (m, 1H), 4.66 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14]S(C2C=CC(C)=CC=2)(=O)=O)[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([OH:34])=[O:33])[C:27]=1[CH3:35].O.[OH-].[Li+].Cl>CO.O.C(OCC)(=O)C>[OH:14][C:5]1[C:4]([CH2:25][C:26]2[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([OH:34])=[O:33])[C:27]=2[CH3:35])=[C:3]([O:2][CH3:1])[C:11]([CH3:12])=[C:10]2[C:6]=1[C:7](=[O:13])[O:8][CH2:9]2
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(CC(=O)O)CC1)C(=O)OC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1c(C)c2c(c(O)c1CC1=C(C)C(CC(=O)O)CC1)C(=O)OC2
Reaction time: 4 h

Procedure:
The 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ylacetic acid obtained in Example ZC-1G was dissolved in a mixture of methanol (8 mL) and water (2 mL) and treated with lithium hydroxide monohydrate (0.15 g). After 4 hours, the reaction was diluted with ethyl acetate and made acidic with 5% hydrochloric acid. After two extractions with ethyl acetate, the product was washed out of the combined organic layers with 2M NaOH. Acidification of the basic layers with 5% hydrochloric acid and extraction of the product into ethyl acetate was followed by drying the organic layer with magnesium sulfate. Filtration and solvent removal was followed by two flash chromatographies (hexanes/ethyl acetate, 4/1 with 1% HOAc; then methylene chloride/methanol 25/1) to provide 3-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ylacetic acid (0.010 g) m.p. 153°-159° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:11]=3[CH:20]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH2:21]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:11]=3[CH:20]=2)[CH2:6][CH2:5]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc2cc(N3CCNCC3)ccc2o1
Reactant: ClCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(N3CCN(Cc4ccccc4)CC3)ccc2o1
Reaction time: 2 h

Procedure:
A solution of 1 g of ethyl 5-(1-piperazinyl)-benzofuran-2-carboxylate in 50 ml of dichloromethane is treated with 1 g of benzyl chloride and stirred for 2 hours. After customary working up, ethyl 5-(4-benzyl-1-piperazinyl)benzofuran-2-carboxylate, m.p. 219°-222°, is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].CC(C)([O-])C.[K+].CCCCCC.C(OCC)(=O)C.Cl>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccccc1OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CCOc1ccccc1C(=O)O
Temperature: 70 °C
Yield: 19.1 %

Procedure:
To a stirred solution of Ethyl 2-Ethoxy-benzoate (10 g, 240 mmol) in dimethyl sulfoxide (40 mL) was added potassium tert-butoxide (10 g, 890 mmol) in portions. The solution was heated to 70° C. on a water bath for 2 h, and the progress of the reaction was monitored by TLC using a hexane-ethyl acetate (8:2) solvent system. The reaction mass was cooled to 10° C., poured into ice water, and then acidified with 5% dilute hydrochloric acid. The precipitated solid was filtered and washed thoroughly with distilled water, and the crude mass was recrystallized in hexane (50 mL) to yield an off-white solid of 2-Ethoxy-benzoic Acid (7.6 g, 80%).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].Br[CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:2]([C:4]1([NH:10][C:11](=[O:12])[CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:5][CH2:6][N:7]([CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH2:8][CH2:9]1)#[N:3]
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Reactant: O=C(O)CCCBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCN(CCCC(=O)O)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride and 4-bromo-butyric acid in the presence of a hindered tertiary amine base such as Hunig's base in a solvent such as methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH:18]=C)=[CH:17][C:12]=3[C:11]3=[N:20][CH:21]=[N:22][N:10]3[C:9]2=[O:23])=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:27].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O.C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH:18]=[O:27])=[CH:17][C:12]=3[C:11]3=[N:20][CH:21]=[N:22][N:10]3[C:9]2=[O:23])=[CH:24][CH:25]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cnc2c(c1)c1ncnn1c(=O)n2Cc1ccc(OC)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C=O)cnc32)cc1
Reaction time: 4 h
Yield: 103.5 %

Procedure:
6-(4-Methoxybenzyl)-9-vinylpyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (3.96 g, 11.9 mmol) was suspended in tetrahydrofuran (80 ml) and heated with a heat gun to effect dissolution. Similarly sodium periodate (5.84 g, 27.3 mmol) was heated in water (40 ml) to effect dissolution. The above solutions were combined with vigorous stifling. While the stirred mixture was still at 40° C., osmium(VIII) oxide in tert-butanol (2.90 ml, 2.5%, 0.30 mmol) was added and the mixture was stirred vigorously for 4 hours. It was diluted with water (300 mL) and extracted with ethyl acetate (3×150 mL) and DCM (3×150 mL). The combined extracts were dried (MgSO4) and concentrated to afford 4.13 g (99%) of the title compound as a black solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.77 (s, 3H), 5.80 (s, 2H), 6.83 (d, J=8.66 Hz, 2H), 7.61 (d, J=8.66 Hz, 2H), 8.41 (s, 1H), 9.10 (d, J=2.13 Hz, 1H), 9.26 (d, J=2.13 Hz, 1H), 10.21 (s, 1H). LCMS (MH+, 336.2).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH2:20][CH2:21][CH2:22][OH:23])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[C:4]([F:24])[CH:3]=1.[C:25](O)(=O)[CH3:26].[CH:29](=O)[CH3:30].C(O[BH3-])(=O)C.[Na+]>CO>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[N:8]([CH2:20][CH2:21][CH2:22][OH:23])[C:7]2[C:2]([N:1]([CH2:25][CH3:26])[CH2:29][CH3:30])=[CH:3][C:4]([F:24])=[CH:5][C:6]=2[N:10]=1
Reactant: CC=O
Reactant: CC(=O)O
Reactant: Nc1cc(F)cc2nc(Nc3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCN(CC)c1cc(F)cc2nc(Nc3ccc(Cl)cc3Cl)n(CCCO)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a suspension of 3-{7-amino-2-[(2,4-dichlorophenyl)amino]-5-fluoro-1H-benzimidazol-1-yl}propan-1-ol (369 mg, 1.00 mmol) and acetic acid (0.5 mL) in methanol (10 mL) was added acetoaldehyde (374 μL, 6.00 mmol) at room temperature. After 30 min, sodium acetoxyborohydride (1.27 g, 6.00 mmol) was added. After 4 h, the mixture was cooled down to 0° C. Then acetic acid (0.5 mL) and acetoaldehyde (374 μL, 6.00 mmol) was added. After 30 min, sodium acetoxyborohydride (1.27 g, 6.00 mmol) was added. After 1 h, the reaction mixture was quenched with water, concentrated in vacuo, diluted with ethyl acetate, washed with aqueous sodium hydroxide (1 M) and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a solid (408 mg, 0.983 mmol, 98%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:28][NH2:29]>O1CCCC1.O>[Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:29][CH3:28])=[CH:16][CH:15]=3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)nc1-c1nnc(-c2ccc(CBr)cc2)o1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNCc1ccc(-c2nnc(-c3nc(Br)cnc3N)o2)cc1
Temperature: 60 °C
Yield: 96.1 %

Procedure:
A suspension of 5-bromo-3-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-amine (2 g, 4.9 mmol) and Na2CO3 (1.55 g, 14.60 mmol) in tetrahydrofuran (30 mL) was treated with methanamine (3.6 mL of 2 M, 7.3 mmol) in THF. The reaction mixture was heated at 60° C. for 1 h. The reaction was cooled, diluted with water and the organic layer was extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to yield 5-bromo-3-(5-(4-((methylamino)methyl)phenyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (1.7 g, 97%) as a yellow solid, which was used without purification in the next step. LC/MS m/z 363.5 [M+H]+.