Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1)(C)C.C([Li])CCC.[F:19][C:20]1[CH:21]=[C:22]([C:27]2([OH:33])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:26][C:24]1[CH:23]=[C:22]([C:27]2([OH:33])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:21]=[C:20]([F:19])[C:25]=1[B:5]1[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:10])([CH3:11])[O:9]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: OC1(c2cc(F)cc(F)c2)CCOCC1
Agent: [Li]CCCC
Product: CC1(C)OB(c2c(F)cc(C3(O)CCOCC3)cc2F)OC1(C)C
Yield: 97 %

Procedure:
Method 3 was followed using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 equiv.), butyllithium (2.4 equiv.) and 4-(3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol (1.0 equiv.) to give 4-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-ol in 97% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.32-1.42 (m, 12 H), 1.56-1.65 (m, 2H), 2.11 (d, J=3.13 Hz, 2 H), 3.86-3.92 (m, 4 H), 6.99 (d, J=9.00 Hz, 2 H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[CH:25]=O)=[CH:19][C:17]=2[CH:18]=1.[O:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][CH:25]=[C:31]3[O:27][C:28](=[O:33])[NH:29][C:30]3=[O:32])=[CH:19][C:17]=2[CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(/C=C/C=O)ccc2o1
Reactant: O=C1COC(=O)N1
Product: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(C=CC=C3OC(=O)NC3=O)ccc2o1
Yield: 44 %

Procedure:
In substantially the same manner as in Example 1, (E)-3-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-yl]acrolein was allowed to react with 2,4-oxazolidinedione to give 5-[3-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-yl]-2-propenylidene]-2,4-oxazolidinedione. The yield was 44%. Recrystallization from dichloromethane-methanol gave pale yellow needles, m.p.237-239° C.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[F:16][C:17]1[CH:18]=[C:19]([N:33]2[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:35][C:34]2=[O:43])[CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]1>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([N:33]2[CH2:37][C@@H:36]([CH2:38][NH+:39]([O-:6])[C:40](=[O:42])[CH3:41])[O:35][C:34]2=[O:43])[CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(S(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Agent: OO
Solvent: ClCCl
Product: CC(=O)[NH+]([O-])C[C@@H]1CN(c2ccc(N3CCN(S(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pertrifluoroacetic acid is prepared in situ by the addition of 30% H2O2 solution (0.15 mL) to trifluoroacetic anhydride (0.45 mL) in 5 mL of methylene chloride at 0° C. This solution is stirred at 0° C. for ten minutes, at 25° C. for 30 minutes and then cooled back to 0° C. (S)-N-[[3-[3-fluoro-4-[4-(methylsulfonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide (VIII-G, R1=COCH3, R9=CH3, X1=F, X2=H) (0.207 g) is added and the reaction is stirred at 25° C. for 30 minutes and then concentrated. The residue is chromatographed on silica gel using 10% methanol (saturated with ammonia) in chloroform as the eluent to afford 0.14 g the N-oxide as a hydrate.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([N:9]1[CH2:14][C@@H:13]2[CH2:15][CH2:16][C@H:10]1[CH2:11][NH:12]2)=[O:8])([CH3:5])([CH3:4])[CH3:3].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:2]([O:6][C:7]([N:9]1[CH2:14][C@@H:13]2[CH2:15][CH2:16][C@H:10]1[CH2:11][N:12]2[C:17](=[O:19])[CH3:18])=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H]1CN2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C[C@@H]2CC[C@H]1CN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of (S,S)-2,5-diaza-bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester hydrochloride (645 mg, 2.59 mmol) in DCM (26 mL) was added acetic anhydride (490 μL, 5.19 mmol) and triethylamine (1.08 mL, 7.77 mmol) and the mixture was stirred (rt, 16 h). The reaction mixture was washed with water (3×8 mL) and brine (1×8 mL). The organic layer was dried, filtered and concentrated in vacuo to provide (S,S)-5-acetyl-2,5-diaza-bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (658 mg, 100%). This intermediate was dissolved in DCM (3.5 mL), treated with HCl (4 M in dioxane, 3.5 mL) and stirred (rt, 16 h). The dispersion was concentrated in vacuo to provide the title compound as a beige powder (494 mg, 100%). MS (ESI): mass calcd. for C8H14N2O, 154.11; m/z found, 155.2 [M+H]+. 1H NMR (500 MHz, MeOD): 4.71 (s, 0.5H), 4.25 (s, 0.5H), 3.97 (dt, J=12.1, 2.8, 0.5H), 3.87 (d, J=2.6, 1H), 3.84-3.73 (m, 1H), 3.68 (m, 1H), 3.64 (dd, J=13.8, 1.6, 0.5H), 3.54 (m, 0.5H), 3.45 (m, 1.5H), 2.12 (m, 4.5H), 2.06-1.91 (m, 2.5H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([NH2:13])=[C:8]([CH3:14])[CH:7]=2)[CH2:4][CH2:3]1.[CH3:15][C:16]1[C:20]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[C:19]([CH3:33])[O:18][N:17]=1.C(N=C(N(C)C)N(C)C)(C)(C)C>N1C=CC=CC=1.CO>[CH:2]1([CH2:5][C:6]2[CH:7]=[C:8]([CH3:14])[C:9]([NH:13][S:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH2:21][C:20]4[C:16]([CH3:15])=[N:17][O:18][C:19]=4[CH3:33])=[CH:28][CH:27]=3)(=[O:30])=[O:31])=[C:10]([CH3:12])[CH:11]=2)[CH2:3][CH2:4]1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(CC2CC2)cc(C)c1N
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1cc(CC2CC2)cc(C)c1NS(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Yield: 3.6 %

Procedure:
To a solution of [4-(cyclopropylmethyl)-2,6-dimethylphenyl]amine hydrochloride (100 mg, 0.472 mmol) and 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (157 mg, 0.520 mmol) in Pyridine (1 mL) was added neat Barton's base (2-(tert-butyl)-1,1,3,3-tetramethylguanidine) (0.095 mL, 0.472 mmol). The reaction vessel was sealed and heated in Emrys Optimiser using initial high absorbance to 100° C. for 30 min. After cooling the reaction was analysed and product presence confirmed. The solvent was evaporated in vacuo using the Vaportec V10 to give the crude product. The sample was loaded in methanol and purified by SPE on aminopropyl (NH2) 5 g using methanol. The appropriate fractions were concentrated and the crude material further purified by SPE on sulfonic acid (SCX) 2 g using methanol. The appropriate fractions were combined and dried under a stream of nitrogen in the Radleys blowdown apparatus to give the crude product. The samples were dissolved in 1:1 MeOH:DMSO 1 mL and purified by mass directed autoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the required products (7.4 mg, 0.017 mmol, 3.56% yield)
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:14][CH3:15])[C:5]2[CH:6]=[CH:7][O:8][C:4]=2[C:3]=1[O:16][CH3:17].O.[OH-].[Na+].[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:14][CH3:15])[C:5]2[CH2:6][CH2:7][O:8][C:4]=2[C:3]=1[O:16][CH3:17]
Reactant: [H][H]
Reactant: COc1c(C(=O)O)c(O)c(OC)c2occc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c(O)c(C(=O)O)c(OC)c2c1OCC2
Yield: 73.4 %

Procedure:
5 g of 6-hydroxy-4,7-dimethoxybenzofuran-5-carboxylic acid in 75 ml of ethanol/25 ml of H2O/0.8 g of NaOH are hydrogenated in the presence of 1 g of Pd/C (10%) under atmospheric pressure and at 50° C. until uptake of hydrogen is complete. The mixture is filtered, the ethanol is removed by distillation, the aqueous phase is acidified, and the solid is filtered off with suction. 3.7 g of product are obtained and reacted further without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=1)=[O:9].C(N(CCN[C:35]([C:37]1[CH:46]=[N:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([I:47])[CH:43]=2)[N:38]=1)=[O:36])CCOC1C(F)=NC=CC=1)C>>[CH2:17]([N:4]([CH2:3][CH2:2][NH:1][C:35]([C:37]1[CH:46]=[N:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([I:47])[CH:43]=2)[N:38]=1)=[O:36])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=1)=[O:9])[CH3:18]
Reactant: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Reactant: CCN(CCN)CCNC(=O)c1ccnc(F)c1
Product: CCN(CCNC(=O)c1ccnc(F)c1)CCNC(=O)c1cnc2cc(I)ccc2n1
Yield: 63 %

Procedure:
This compound was prepared, starting from compound 38 (0.26 g, 1.02 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 24 h; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 98/2, v/v) to give compound 39 (236 mg, 0.45 mmol) as a beige solid. Yield 63%; Rf (Al2O3, CH2Cl2/EtOH, 98/2, v/v) 0.50; mp 146-148° C.; IR (KBr) ν 1524, 1542, 1662, 2800-3000, 3335, 3388 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.02 (t, 3H, J=7.1 Hz), 2.65 (q, 2H, J=7.1 Hz), 2.79 (m, 4H), 3.59 (m, 4H), 7.33 (s, 1H), 7.52 (d, 1H, J=5.1 Hz), 7.64 (d, 2H, J=8.8 Hz), 8.01 (dd, 1H, J=1.7, 8.8 Hz), 8.14 (d, 1H, J=5.1 Hz), 8.22 (m, 1H), 8.55 (d, 1H, J=1.7 Hz), 9.48 (s, 1H); ESI-MS m/z 537.0 [M+H]+.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:10][C:9]([CH2:17][NH2:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].CCN(C(C)C)C(C)C.[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31]([NH:18][CH2:17][C:9]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:10][N:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:5])=[O:6])[CH2:8]1)=[O:32]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCCS(=O)(=O)N1CC(CN)(c2ccccn2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CC(CNC(=O)c2ccc(Cl)cc2Cl)(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-[1-(propylsulfonyl)-3-pyridin-2-ylazetidin-3-yl]methanamine (II-2, 10 mg, 0.04 mmol) in CH2Cl2 (1 mL) was treated with i-Pr2NEt (0.1 mL, 0.58 mmol), 2,4-dichlorobenzoyl chloride (20 μL, 0.14 mmol), and stirred at room temperature. After 3 h, volatiles were removed under a stream of N2 and the residue purified by reverse phase HPLC to afford 2,4-dichloro-N-{[1-(propylsulfonyl)-3-pyridin-2-ylazetidin-3-yl]methyl}benzamide (II-3) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]#[N:13])=[CH:10][C:4]=2[O:3]1.Br[CH2:16][CH2:17]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:14][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:12]#[N:13])[CH2:17][CH2:16]3)=[CH:10][C:4]=2[O:3]1
Reactant: N#CCc1ccc2c(c1)OC(F)(F)O2
Reactant: ClCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: N#CC1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A stock solution of 50% w/w NaOH was degassed via nitrogen sparge for no less than 16 h. An appropriate amount of MTBE was similarly degassed for several hours. To a reactor purged with nitrogen was charged degassed MTBE (143 mL) followed by (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (40.95 g, 207.7 mmol) and tetrabutylammonium bromide (2.25 g, 10.38 mmol). The volume of the mixture was noted and the mixture was degassed via nitrogen sparge for 30 min. Enough degassed MTBE is charged to return the mixture to the original volume prior to degassing. To the stirring mixture at 23.0° C. was charged degassed 50% w/w NaOH (143 mL) over 10 min followed by 1-bromo-2-chloroethane (44.7 g, 311.6 mmol) over 30 min. The reaction was analyzed by HPLC in 1 h intervals for % conversion. Before sampling, stirring was stopped and the phases allowed to separate. The top organic phase was sampled for analysis. When a conversion>99% was observed (typically after 2.5-3 h), the reaction mixture was cooled to 10° C. and was charged with water (461 mL) at such a rate as to maintain a temperature <25° C. The temperature was adjusted to 20-25° C. and the phases separated. Note: sufficient time should be allowed for complete phase separation. The aqueous phase was extracted with MTBE (123 mL), and the combined organic phase was washed with 1 N HCl (163 mL) and 5% NaCl (163 mL). The solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile in MTBE was concentrated to 164 mL under vacuum at 40-50° C. The solution was charged with ethanol (256 mL) and again concentrated to 164 mL under vacuum at 50-60° C. Ethanol (256 mL) was charged and the mixture concentrated to 164 mL under vacuum at 50-60° C. The resulting mixture was cooled to 20-25° C. and diluted with ethanol to 266 mL in preparation for the next step. 1H NMR (500 MHz, DMSO) δ 7.43 (d, J=8.4 Hz, 1H), 7.40 (d, J=1.9 Hz, 1H), 7.30 (dd, J=8.4, 1.9 Hz, 1H), 1.75 (m, 2H), 1.53 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:9]=2)=[CH:5][CH:4]=1)#[N:2].[C:27]([O:31][C:32](=[O:42])[NH:33][CH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:42])[NH:33][CH2:34][CH2:35][CH:36]1[CH2:37][CH2:38][N:39]([C:12]([C:11]2[C:10]([O:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:9][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:26][CH:25]=3)=[CH:16][CH:15]=2)=[O:13])[CH2:40][CH2:41]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(F)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(F)cc2)CC1
Yield: 78.2 %

Procedure:
6-(4-cyano phenoxy)-2-(4-fluoro phenoxy)nicotinic acid (0.2 g, 0.57 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.13 g, 0.57 mmol) were coupled using the procedure of Example 5(c) to afford 0.25 g of the required product. Percentage purity: LCMS (−ve mode): 67.5%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[H-].[Na+].C(OP([CH2:26][C:27]([O:29]CC)=[O:28])(OCC)=O)C.CN(C)C=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cn1ncc(C=O)c1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc(/C=C/C(=O)O)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
A mixture of 5-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (350 mg), sodium hydride (60% in oil, 120 mg), ethyl diethylphosphonoacetate (673 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the precipitated solids were collected by filtration. After drying with airflow, the solids were dissolved in a mixed solvent of tetrahydrofuran (10 ml) and ethanol (10 ml). A 1N aqueous sodium hydroxide solution (5 ml) was added and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into a 10% aqueous citric acid solution and the precipitated solids were collected by filtration, washed with water and dried with airflow to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (354 mg, 84%) as crystals. Recrystallization thereof from methanol-isopropyl ether gave colorless prism crystals. melting point: 212-213° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].O.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=1[C:24](Cl)=[O:25]>O1CCOCC1>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=1[C:24]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:25]
Reactant: NCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 43 gm (20.1 millimols) of 4-[2-Aminoethyl]-4'-hydroxy-biphenyl in a mixture of 8.5 gm (21.3 millimols) of sodium hydroxide, 270 ml of water and 100 ml of dioxane, was acylated with 41.5 gm (20.1 millimols) of 2-methoxy-5-chloro-benzoyl chloride at 0° C. After stirring at room temperature for 2 hours, the mixture was extracted with chloroform, and the organic phase was dried over sodium sulfate. After distilling off the extracting agent, 72 gm (94% of theory) of a light yellow oil were obtained. This oil crystallized slowly and was uniform in the thin-layer chromatogram (silicagel; eluant: benzene/ethyl acetate = 7:2). After purification by column chromatography on silicagel with benzene/ethyl acetate as the eluant, the oil crystallized slowly. M.p. 169° C
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:18](=[N:19][OH:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:27]([O:29][C:30](=[O:37])[CH2:31][NH:32][C:33](=[O:36])[CH2:34]Br)[CH3:28].O>CN(C=O)C>[CH2:27]([O:29][C:30](=[O:37])[CH2:31][NH:32][C:33](=[O:36])[CH2:34][O:20][N:19]=[C:18]1[C:5]2[C:6](=[N:7][C:8]([C:9](=[O:10])[NH2:11])=[C:3]([C:1]#[N:2])[N:4]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]1=2)[CH3:28]
Reactant: CCOC(=O)CNC(=O)CBr
Reactant: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=NO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNC(=O)CON=C1c2ccccc2-c2nc(C(N)=O)c(C#N)nc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.2 %

Procedure:
To a suspension of 33 (212 mg, 0.80), Cs2CO3 (260 mg, 0.80) in DMF (15 ml), 39 (200 mg, 0.89 mmol) was added portionwise and the mixture was stirred at room temperature for 2 days. H2O (30 ml) was added and the suspension was extracted with CH2Cl2 (70 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography (CH2Cl2/MeOH 9:1) affording 40 (56 mg, 17%) as yellow-brown solid. 1H NMR (300 MHz, DMSO d6): δ 8.78 (m, 2H), 8.12 (bs, 1H), 8.05-7.78 (m, 3H), 7.67 (m, 1H), 4.72 and 4.69 (s, 2H), 4.10 (q, 2H), 3.92 and 3.90 (s, 2H), 1.19 (t, 3H). ESI+MS: calcd for C19H16N6O5: 408.38; found: 409.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][C:9]=2[CH3:18])=[O:5])[CH3:2].[H][H]>O1CCCC1.CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH2:15])=[CH:10][C:9]=2[CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])cc(C)c2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(N)cc(C)c2[nH]1

Procedure:
A mixture of 5 g 7-methyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester and 0.5 g Pd/C 10% in 200 ml tetrahydrofuran/methanol (3:1) was stirred for 5 h under a pressure of 3 bar of hydrogen. The catalyst was filtered and the mixture was evaporated under reduced pressure. The residue was purified by silica gel chromatography (SiO2; cyclohexane/ethyl acetate 75:25→50:50).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24].CN1CCOCC1>CO>[F:21][C:22]([F:26])([F:25])[CH2:23][NH:24][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCC(F)(F)F
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCC(F)(F)F)cc2s1
Yield: 9.4 %

Procedure:
the title compound (11 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 2,2,2-trifluoroethylamine (48 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 392.4 (M+1, 100%). Yield=9%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CCCCCC.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:31])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cccc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Combine 2-(3-bromophenyl)-1,3-dioxolane (10.0 ml, 66.0 mmol) and tetrahydrofuran (100 ml) and cool to about −78° C. Add dropwise a solution of n-butyllithium, 1.6 M solution in hexane (44.0 ml, 66.0 mmol). After 10 min, add a solution of benzaldehyde (7.6 ml, 66.0 mmol) in tetrahydrofuran (50 ml) via cannula. After 1 hour, warm to room temperature. After 18 hours, quench into water and extract with dichloromethane. Combine the organic layers and wash sequentially with distilled water and brine and then dry (Na2SO4), filter, and concentrate to give a residue. Chromatograph the residue eluting with 7:3 hexane:EtOAc to give the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C@H:6]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:7][OH:8])=[O:4].[CH2:21]=[C:22]1[O:26][C:24](=[O:25])[CH2:23]1>O1CCCC1>[C:24]([O:8][CH2:7][C@@H:6]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[NH:5][C:3](=[O:4])[C:2]([F:19])([F:20])[F:1])(=[O:25])[CH2:23][C:22]([CH3:21])=[O:26]
Reactant: O=C(OCc1ccccc1)[C@H](CO)NC(=O)C(F)(F)F
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1

Procedure:
A solution of benzyl trifluoroacetyl-L-serinate (500 mg) and diketene (0.1 ml) in tetrahydrofuran (10 ml) was heated with reflux overnight. The solvent was distilled off and the residue was diluted with ethyl acetate and washed successively with water and brine. After drying over sodium sulfate, the ethyl acetate extract was filtered and concentrated. The residue was chromatographed on silica gel eluting successively with methylene chloride and a 4:1 mixture of methylene chloride and acetone to give benzyl O-acetoacetyl-N-trifluoroacetyl-L-serinate (320 mg).
Reaction SMILES: C[Sn](C)(C)[C:3]1[C:11]2[C:10]([Cl:12])=[N:9][CH:8]=[N:7][C:6]=2[NH:5][CH:4]=1.[F:15][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>CC#N>[F:15][C:3]1[C:11]2[C:10]([Cl:12])=[N:9][CH:8]=[N:7][C:6]=2[NH:5][CH:4]=1
Reactant: F[B-](F)(F)F
Reactant: C[Sn](C)(C)c1c[nH]c2ncnc(Cl)c12
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Fc1c[nH]c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of the compound from Step B (1.97 g, 6.20 mmol) in CH3CN (60 mL) was added [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] (SELECTFLUOR® fluorinating reagent) (2.40 g, 6.5 mmol) in one portion and the reaction mixture was stirred at room temperature for 7 h. The white precipitate was filtered off, and the filtrate was evaporated to dryness. The residue was purified over silica gel using ethyl acetate/hexane (3:7) as the eluent. Fractions containing the product were pooled and eveporated in vacuo to give the title compound as a colorless solid.